Ligand/receptor specificity exchangers that redirect antibodies to receptors on a pathogen

ABSTRACT

The present invention generally relates to compositions and methods for preventing and treating human diseases including, but not limited to, pathogens such as bacteria, yeast, parasites, fungus, viruses, and cancer. More specifically, embodiments described herein concern the manufacture and use of ligand/receptor specificity exchangers, which redirect existing antibodies in a subject to receptors present on pathogens.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 09/532,106, filed on Mar. 21, 2000, now U.S. Pat. No.6,245,895; which is a continuation of U.S. patent application Ser. No.09/246,258, filed on Feb. 8, 1999, now U.S. Pat. No. 6,040,137; which isa continuation of U.S. patent application Ser. No. 08/737,085, filed onDec. 27, 1996, now U.S. Pat. No. 5,869,232; which was a national phaseapplication of PCT/SE 95/00468, filed on Apr. 27, 1995 that designatedthe United States of America and was published in English, and claimedpriority to Swedish Patent Application No. 9401460, filed on Apr. 28,1994. This application claims priority to U.S. patent application Ser.Nos. 09/532,106; 09/246,258; 08/737,085; PCT/SE 9500468; and SwedishPatent Application No. 9401460, all of which are hereby expresslyincorporated by reference in their entireties.

FIELD OF THE INVENTION

The present invention generally relates to compositions and methods forpreventing and treating human diseases including, but not limited to,pathogens such as bacteria, yeast, parasites, fungus, viruses, andcancer. More specifically, embodiments described herein concern themanufacture and use of ligand/receptor specificity exchangers, whichredirect existing antibodies in a subject to receptors present onpathogens.

BACKGROUND OF THE INVENTION

Infection by pathogens, such as bacteria, yeast, parasites, fungus, andviruses, and the onset and spread of cancer present serious healthconcerns for all animals, including humans, farm livestock, andhousehold pets. These health threats are exacerbated by the rise ofstrains that are resistant to vaccination and/or treatment. In the past,practitioners of pharmacology have relied on traditional methods of drugdiscovery to generate safe and efficacious compounds for the treatmentof these diseases. Traditional drug discovery methods typically involveblindly testing potential drug candidate-molecules, often selected atrandom, in the hope that one might prove to be an effective treatmentfor some disease. With the advent of molecular biology, however, thefocus of drug discovery has shifted to the identification of moleculartargets associated with the etiological agent and the design ofcompounds that interact with these molecular targets.

One promising class of molecular targets are the receptors found on thesurface of bacteria, yeast, parasites, fungus, viruses, and cancercells, especially receptors that allow for attachment to a host cell orhost protein (e.g., an extracellular matrix protein). Research in thisarea primarily focuses on the identification of the receptor and itsligand and the discovery of molecules that interrupt the interaction ofthe ligand with the receptor and, thereby, block adhesion to the hostcell or protein. Although several receptor antagnosists have promisingtherapeutic potential, there still remains a need for new compositionsand methods to treat and prevent infection by pathogens and otherdiseases.

BRIEF SUMMARY OF THE INVENTION

The invention described herein concerns the manufacture,characterization, and use of novel agents that bind receptors onpathogens and redirect antibodies present in a subject to the pathogen.Embodiments include a ligand/receptor specificity exchanger having atleast one specificity domain comprising a ligand for a receptor and atleast one antigenic domain joined to said specificity domain, whereinsaid antigenic domain comprises an epitope of a pathogen or toxin.

Some embodiments of the ligand/receptor specificity exchanger have aspecificity domain that comprises at least three consecutive amino acidsof a peptide selected from the group consisting of an extracellularmatrix protein, a ligand for a receptor on a virus, and a ligand for areceptor on a cancer cell. In some aspects of this embodiment, forexample, the peptide is an extracellular matrix protein selected fromthe group consisting of fibrinogen, collagen, vitronectin, laminin,plasminogen, thrombospondin, and fibronectin. Preferably, theextracellular matrix protein comprises at least 3 amino acids of thealpha-chain of fibrinogen and in the most preferred embodiments theligand comprises the sequence Arginine-Glycine-Aspartate (RGD).

In other embodiments, the peptide described above is a ligand for areceptor on a virus selected from the group consisting of T4glycoprotein and hepatitis B viral envelope protein. In still otheraspects of this embodiment, the peptide is a ligand for a receptor on acancer cell selected from the group consist of a ligand for HER-2/neuand a ligand for an integrin receptor. Preferred embodiments have aspecificity domain that comprises a sequence provided by one of SEQ. ID.Nos. 1-42.

The ligand/receptor specificity exchangers described herein interactwith a receptor found on a pathogen. In some embodiments, the receptoris a bacterial adhesion receptor, for example, a bacterial adhesionreceptor selected from the group consisting of extracellular fibrinogenbinding protein (Efb), collagen binding protein, vitronectin bindingprotein, laminin binding protein, plasminogen binding protein,thrombospondin binding protein, clumping factor A (ClfA), clumpingfactor B (ClfB), fibronectin binding protein, coagulase, andextracellular adherence protein.

The ligand/receptor specificity exchangers described herein alsointeract with a an antibody present in a subject. In some embodiments,for example, the antigenic domain comprises at least three amino acidsof a peptide selected from the group consisting of a herpes simplexvirus protein, a hepatitis B virus protein, a TT virus protein, and apoliovirus protein. In desirable embodiments, the ligand/receptorspecificity exchanger has an antigenic domain that is a herpes simplexvirus protein comprising a sequence selected from the group consistingof SEQ. ID. No. 53 and SEQ. ID. No. 54. In other desired embodiments,the antigenic domain is a hepatitis B virus protein comprising asequence provided by one of SEQ. ID. No. 49, SEQ. ID. No. 50, SEQ. ID.No. 52, and SEQ. ID. No. 59.

Some ligand/receptor specificity exchangers also have an antigenicdomain that is a TT virus protein comprising a sequence provided by oneof SEQ. ID. Nos. 43-47 and SEQ. ID. Nos. 55-58. The ligand/receptorspecificity exchangers can also have an antigenic domain that is a poliovirus protein comprising a sequence selected from the group consistingof SEQ. ID. No. 48 and SEQ. ID. No. 51. Preferably, the ligand/receptorspecificity exchanger has an antigenic domain that interacts with ahigh-titer antibody. In some embodiments, for example, the antigenicdomain specifically binds to an antibody present in animal serum thathas been diluted to between approximately 1:100 to 1:1000 or greater.The specificity exchangers of SEQ. ID. Nos. 60-105 are embodiments ofthe invention.

Aspects of the invention also concern method of treating or preventing ainfection or proliferation of a pathogen. One approach for example,involves a method for treating and preventing bacterial infection. Thismethod is practiced by providing a therapeutically effective amount of aligand/receptor specificity exchanger to a subject, wherein saidligand/receptor specificity exchanger comprises a specificity domainthat has a ligand that interacts with a receptor on a bacteria, and anantigenic domain that comprises an epitope for a pathogen or toxin. Amethod of treating or preventing viral infection is also an embodiment.Accordingly, a method of treating or preventing a viral infection ispracticed by providing a therapeutically effective amount of aligand/receptor specificity exchanger to a subject, wherein saidligand/receptor specificity exchanger comprises a specificity domainthat has a ligand that interacts with a receptor on a virus, and anantigenic domain that comprises an epitope for a pathogen or toxin.Similarly, a method of treating or preventing cancer is an embodimentand this method can be practiced by providing a therapeuticallyeffective amount of a ligand/receptor specificity exchanger to asubject, wherein said ligand/receptor specificity exchanger comprises aspecificity domain that has a ligand that interacts with a receptor on acancer cell, and an antigenic domain that comprises an epitope for apathogen or toxin.

DETAILED DESCRIPTION OF THE INVENTION

The following describes the manufacture, characterization, and use ofnovel agents that bind receptors on pathogens and redirect antibodiespresent in a subject to the pathogen. The embodiments are collectivelyreferred to as “ligand/receptor specificity exchangers”. The term“ligand/receptor specificity exchangers” refers a specificity exchangerthat comprises a “specificity domain” that has at least one ligand for areceptor (a “ligand” is not an antibody or portion thereof) joined to an“antigenic domain” that has at least one epitope of a pathogen or toxin(e.g., pertussis toxin or cholera toxin).

The ligand/receptor specificity exchangers can comprise more than aspecificity domain and an antigenic domain. For example, someligand/receptor specificity exchangers comprise a plurality ofspecificity domains and/or antigenic domains. Ligand/receptorspecificity exchangers having multiple specificity domains and/orantigenic domains are said to be “multimerized” because more than onespecificity domain and/or antigenic domain are fused in tandem. Otherembodiments concern ligand/receptor specificity exchangers that contain,in addition to a specificity domain and an antigenic domain, sequencesthat facilitate purification (e.g., a poly histidine tail), linkers(e.g., biotin and/or avidin or streptavidin or the flexible arms of λphage (λ-linkers)), and sequences or modifications that either promotethe stability of the ligand/receptor specificity exchanger (e.g.,modifications that provide resistance to protease digestion) or promotethe degradation of the ligand/receptor specificity exchanger (e.g.,protease cleavage sites). Although the specificity and antigenic domainsare preferably peptides; some ligand/receptor specificity exchangershave specificity and antigenic domains that are made of modified orderivatized peptides, peptidomimetics, or chemicals.

The diversity of ligand/receptor specificity exchangers is vast becausethe embodiments described herein can bind to many different receptors onmany different pathogens. Thus, the term “pathogen” is used herein in ageneral sense to refer to an etiological agent of disease in animalsincluding, but not limited to, bacteria, parasites, fungus, mold,viruses, and cancer cells. Similarly, the term “receptor” is used in ageneral sense to refer to a molecule (usually a peptide other than asequence found in an antibody, but can be a carbohydrate, lipid, ornucleic acid) that interacts with a “ligand” (usually a peptide otherthan a sequence found in an antibody, or a carbohydrate, lipid, nucleicacid or combination thereof). A “receptor”, as used herein, does nothave to undergo signal transduction and can be involved in a number ofmolecular interactions including, but not limited to, adhesion (e.g.,integrins) and molecular signaling (e.g., growth factor receptors). Forexample, desired specificity domains comprise a ligand that has apeptide sequence that is present in an extracellular matrix protein(e.g., fibrinogen, collagen, vitronectin, laminin, plasminogen,thrombospondin, and fibronectin) and some specificity domains comprise aligand that interacts with a bacterial adhesion receptor (e.g.,extracellular fibrinogen binding protein (Efb), collagen bindingprotein, vitronectin binding protein, laminin binding protein,plasminogen binding protein, thrombospondin binding protein, clumpingfactor A (ClfA), clumping factor B (ClfB), fibronectin binding protein,coagulase, and extracellular adherence protein).

In other embodiments, the specificity domain comprises a ligand that hasa peptide sequence that interacts with a viral receptor (e.g., afragment of T4 glycoprotein that binds gp120 or a fragment of the preSdomain, which binds gp170 of the hepadnavirus family). In still otherembodiments, the specificity domain comprises a ligand that interactswith a receptor on a cancer cell (e.g., HER-2/neu (C-erbB2)) or anintegrin receptor such as a vitronectin receptor, a laminin receptor, afibronectin receptor, a collagen receptor, a fibrinogen receptor, anα₄β₁ receptor, an α₆β₁ receptor, an α₃β₁ receptor, an α₅β₁ receptor, andan α_(v)β₃ receptor. Preferred embodiments, however, have a specificitydomain that comprises at least 8 amino acids of the alpha-chain offibrinogen and/or the sequence Arginine-Glycine-Aspartic acid (RGD) andthe most preferred embodiments have a specificity domain that comprisesa sequence selected from the group consisting of SEQ. ID. Nos. 60-105.

Desired antigenic domains have an epitope that is recognized by anantibody that already exists in a subject. For example, many people areimmunized against childhood diseases including, but not limited to,small pox, measles, mumps, rubella, and polio. Thus, antibodies toepitopes on these pathogens can be produced by an immunized person.Desirable antigenic domains have an epitope that is found on one ofthese etiological agents.

Some embodiments have antigenic domains that interact with an antibodythat has been administered to the subject. For example, an antibody thatinteracts with an antigenic domain on a ligand/receptor specificityexchanger can be co-administered with the ligand/receptor specificityexchanger. Further, an antibody that interacts with a ligand/receptorspecificity exchanger may not normally exist in a subject but thesubject has acquired the antibody by introduction of a biologic material(e.g., serum, blood, or tissue). For example, subjects that undergoblood transfusion acquire numerous antibodies, some of which caninteract with an antigenic domain of a ligand/receptor specificityexchanger.

The most desirable antigenic domains comprise an epitope that isrecognized by a high titer antibody. By “high titer antibody” is meantan antibody that has high affinity for an antigen (e.g., an epitope onan antigenic domain). For example, in a solid-phase enzyme linkedimmunosorbent assay (ELISA), a high titer antibody corresponds to anantibody present in a serum sample that remains positive in the assayafter a dilution of the serum to approximately the range of 1:100-1:1000in an appropriate dilution buffer, preferably, about 1:500. Thepreferred antigenic domains, however, have an epitope found on herpessimplex virus gG2 protein, hepatitis B virus s antigen (HBsAg),hepatitis B virus e antigen (HBeAg), hepatitis B virus c antigen(HBcAg), TT virus, and the poliovirus or combination thereof or comprisea sequence selected from the group consisting of SEQ. ID. Nos. 43-59.

The ligand/receptor specificity exchangers described herein can be madeby conventional techniques in recombinant engineering and/or peptidechemistry. In some embodiments, the specificity and antigenic domainsare made separately and are subsequently joined together (e.g., throughlinkers or by association with a common carrier molecule). In otherembodiments, the specificity domain and antigenic domain are made aspart of the same molecule. By one approach, a ligand/receptorspecificity exchanger having a specificity domain joined to an antigenicdomain is made by a peptide synthesizer. By another approach, a nucleicacid encoding the specificity domain fused to an antigenic domain iscloned into an expression construct, transfected to cells, and theligand/receptor specificity exchanger is purified or isolated from thecells or cell supernatent.

Once the ligand/receptor specificity exchanger is made, it can bescreened to determine its ability to interact with the receptor on thepathogen and/or an antibody specific for the antigenic domain. Thus, theterm “characterization assay” is used to refer to an experiment orevaluation of the ability of a ligand/receptor specificity exchanger tointeract with a receptor on a pathogen or cancer cell or fragmentthereof and/or an antibody specific for the antigenic domain. Somecharacterization assays, for example, evaluate the ability of aligand/receptor specificity exchanger to bind to a support having areceptor of a pathogen or fragment thereof disposed thereon or viceversa. Other characterization assays assess the ability of aligand/receptor specificity exchanger to bind to an antibody specificfor the antigenic domain of the ligand/receptor specificity exchanger.Still other characterization assays evaluate the ability of theligand/receptor specificity exchanger to effect infection by thepathogen or cancer cell proliferation in cultured cell lines or diseasedanimals.

The ligand/receptor specificity exchangers described herein can be usedas the active ingredients in pharmaceuticals for the treatment andprevention of pathogenic infection, as well as cancer, in animalsincluding humans. The pharmaceutical embodiments can be formulated inmany ways and may contain excipients, binders, emulsifiers, carriers,and other auxiliary agents in addition to the ligand/receptorspecificity exchanger. Pharmaceuticals comprising a ligand/receptorspecificity exchanger can be administered by several routes including,but not limited to, topical, transdermal, parenteral, gastrointestinal,transbronchial, and transalveolar. Ligand/receptor specificityexchangers can also be used as a coating for medical equipment andprosthetics to prevent infection or the spread of disease. The amount ofligand/receptor specificity exchanger provided in a pharmaceutical,therapeutic protocol, or applied to a medical device varies depending onthe intended use, the patient, and the frequency of administration.

Some of the methods disclosed concern the administration of aligand/receptor specificity exchanger to a subject in need of treatmentand/or prevention of bacterial infection, fungal infection, viralinfection, and cancer. By one approach, a subject suffering frombacterial infection is provided a ligand/receptor specificity exchangerthat comprises a specificity domain, which interacts with a bacterialreceptor. Similarly, a subject suffering from a viral infection can beprovided a ligand/receptor specificity exchanger that comprises aspecificity domain that interacts with a viral receptor and a subjectsuffering from cancer is provided a ligand/receptor specificityexchanger that comprises a specificity domain that interacts with areceptor on the cancer cells. Once a receptor/specificity exchangercomplex is formed, it is contemplated that the pathogen or cancer cellis cleared from the body by complement fixation and/or macrophagedegradation.

Methods of treatment and prevention of disease (e.g., bacterial, fungal,and viral infection, and cancer) are provided in which a subjectsuffering from disease or a subject at risk for contracting a disease isidentified and then is provided a therapeutically effective amount of aligand/receptor specificity exchanger that interacts with a receptorpresent on the etiological agent. Accordingly, subjects suffering from abacterial infection, fungal infection, viral infection, or cancer areidentified by conventional clinical and diagnostic evaluation and areprovided a therapeutically effective amount of a ligand/receptorspecificity exchanger that interacts with the particular pathogen orcancer cell. Although the ligand/receptor specificity exchangersdescribed herein can be administered to all animals at risk of diseasefor prophylactic purposes, it may be desired to administer theligand/receptor specificity exchangers only to those individuals thatare in a high risk category (e.g., infants, the elderly, and those thatcome in close contact with pathogens). As stated above, high riskindividuals are identified by currently available clinical anddiagnostic techniques.

The section below provides more description of various types ofligand/receptor specificity exchangers that interact with receptors onbacteria, parasites, fungus, mold, viruses, and cancer cells.

Ligand/receptor Specificity Exchangers that Interact with Receptors on aPathogen

The ligand/receptor specificity exchangers that interact with receptorson a pathogen have a variety of chemical structures but, in a generalsense, they are characterized as having at least one region that bindsto the receptor (the specificity domain) and at least one region thatinteracts with an antibody that is specific for an epitope of a pathogenor toxin (the antigenic domain). Preferred ligand/receptor specificityexchangers are peptides but some embodiments comprise derivatized ormodified peptides or a peptidomimetic structure. For example, a typicalpeptide-based ligand/receptor specificity exchanger can be modified tohave substituents not normally found on a peptide or to havesubstituents that are normally found on a peptide but are incorporatedat regions that are not normal. In this vein, a peptide-basedligand/receptor specificity exchanger can be acetylated, acylated, oraminated and the substituents that can be included on the peptide so asto modify it include, but are not limited to, H, alkyl, aryl, alkenyl,alkynl, aromatic, ether, ester, unsubstituted or substituted amine,amide, halogen or unsubstituted or substituted sulfonyl or a 5 or 6member aliphatic or aromatic ring. Thus, the term “ligand/receptorspecificity exchanger” is a broad one that encompasses modified orunmodified peptide structures, as well as peptidomimetics and chemicalstructures.

There are many ways to make a peptidomimetic that resembles apeptide-based ligand/receptor specificity exchanger. The naturallyoccurring amino acids employed in the biological production of peptidesall have the L-configuration. Synthetic peptides can be preparedemploying conventional synthetic methods, utilizing L-amino acids,D-amino acids, or various combinations of amino acids of the twodifferent configurations. Synthetic compounds that mimic theconformation and desirable features of a peptide but that avoid theundesirable features, e.g., flexibility (loss of conformation) and bondbreakdown are known as a “peptidomimetics”. (See, e.g., Spatola, A. F.Chemistry and Biochemistry of Amino Acids. Peptides, and Proteins(Weistein, B, Ed.), Vol. 7, pp. 267-357, Marcel Dekker, New York (1983),which describes the use of the methylenethio bioisostere [CH₂S] as anamide replacement in erikephalin analogues; and Szelke et al., Inpeptides: Structure and Function, Proceedings of the Eighth AmericanPeptide Symposium, (Hruby and Rich, Eds.); pp. 579-582, Pierce ChemicalCo., Rockford, Ill. (1983), which describes renin inhibitors having boththe methyleneamino [CH₂ NH] and hydroxyethylene [CHOHCH₂] bioisosteresat the Leu-Val amide bond in the 6-13 octapeptide derived fromangiotensinogen, all of which are expressly incorporated by reference intheir entireties).

In general, the design and synthesis of a peptidomimetic that resemblesa ligand/receptor specificity exchanger involves starting with thesequence of the ligand/receptor specificity exchanger and conformationdata (e.g., geometry data, such as bond lengths and angles) of a desiredligand/receptor specificity exchanger (e.g., the most probable simulatedpeptide), and using such data to determine the geometries that should bedesigned into the peptidomimetic. Numerous methods and techniques areknown in the art for performing this step, any of which could be used.(See, e.g., Farmer, P. S., Drug Design, (Ariens, E. J. ed.), Vol. 10,pp. 119-143 (Academic Press, New York, London, Toronto, Sydney and SanFrancisco) (1980); Farmer, et al., in TIPS, 9/82, pp. 362-365; Verber etal., in TINS, 9/85, pp. 392-396; Kaltenbronn et al., in J. Med. Chem.33: 838-845 (1990); and Spatola, A. F., in Chemistry and Biochemistry ofAmino Acids. Peptides, and Proteins, Vol. 7, pp. 267-357, Chapter 5,“Peptide Backbone Modifications: A Structure-Activity Analysis ofPeptides Containing Amide Bond Surrogates. Conformational Constraints,and Relations” (B. Weisten, ed.; Marcell Dekker: New York, pub.) (1983);Kemp, D. S., “Peptidomimetics and the Template Approach to Nucleation ofβ-sheets and α-helices in Peptides,” Tibech, Vol. 8, pp. 249-255 (1990),all of which are expressly incorporated by reference in theirentireties). Additional teachings can be found in U.S. Pat. Nos.5,288,707; 5,552,534; 5,811,515; 5,817,626; 5,817,879; 5,821,231; and5,874,529, all of which are expressly incorporated by reference in theirentireties. Once the peptidomimetic is designed, it can be made usingconventional techniques in peptide chemistry and/or organic chemistry.

Some embodiments comprise a plurality of specificity domains and/or aplurality of antigenic domains. One type of ligand/receptor specificityexchanger that has a plurality of specificity domains and/or antigenicdomains is referred to as a “multimerized ligand/receptor specificityexchanger” because it has multiple specificity domains and/or antigenicdomains that appear in tandem on the same molecule. For example, amultimerized specificity domain may have two or more ligands thatinteract with one type of receptor, two or more ligands that interactwith different types of receptors on the pathogen, and two or moreligands that interact with different types of receptors on differentpathogens.

Similarly, a multimerized antigenic domain can be constructed to havemultimers of the same epitope of a pathogen or different epitopes of apathogen, which can also be multimerized. That is, some multimerizedantigenic domains are multivalent because the same epitope is repeated.In contrast, some multimerized antigenic domains have more than oneepitope present on the same molecule in tandem but the epitopes aredifferent. In this respect, these antigenic domains are multimerized butnot multivalent. Further, some multimerized antigenic domains areconstructed to have different epitopes but the different epitopes arethemselves multivalent because each type of epitope is repeated.

Some ligand/receptor specificity exchangers comprise other elements inaddition to the specificity domain and antigenic domain such assequences that facilitate purification, linkers that provide greaterflexibility and reduce steric hindrance, and sequences that eitherprovide greater stability to the ligand/receptor specificity exchanger(e.g., resistance to protease degradation) or promote degradation (e.g.,protease recognition sites). For example, the ligand/receptorspecificity exchangers can comprise cleavable signal sequences thatpromote cytoplasmic export of the peptide and/or cleavable sequence tagsthat facilitate purification on antibody columns, glutathione columns,and metal columns.

Ligand/receptor specificity exchangers can comprise elements thatpromote flexibility of the molecule, reduce steric hindrance, or allowthe ligand/receptor specificity exchanger to be attached to a support orother molecule. These elements are collectively referred to as“linkers”. One type of linker that can be incorporated with aligand/receptor specificity exchanger, for example, is avidin orstreptavidin (or their ligand—biotin). Through abiotin-avidin/streptavidin linkage, multiple ligand/receptor specificityexchangers can be joined together (e.g., through a support, such as aresin, or directly) or individual specificity domains and antigenicdomains can be joined. Another example of a linker that can be includedin a ligand/receptor specificity exchanger is referred to as a “λlinker” because it has a sequence that is found on λ phage. Preferred λsequences are those that correspond to the flexible arms of the phage.These sequences can be included in a ligand/receptor specificityexchanger (e.g., between the specificity domain and the antigenic domainor between multimers of the specificity and/or antigenic domains) so asto provide greater flexibility and reduce steric hindrance.

Additionally, ligand/receptor specificity exchangers can includesequences that either confer resistance to protease degradation orpromote protease degradation. By incorporating multiple cysteines in aligand/receptor specificity exchanger, for example, greater resistanceto protease degradation can be obtained. These embodiments of theligand/receptor specificity exchanger are expected to remain in the bodyfor extended periods, which may be beneficial for some therapeuticapplications. In contrast, ligand/receptor specificity exchangers canalso include sequences that promote rapid degradation so as to promoterapid clearance from the body. Many sequences that serve as recognitionsites for serine, cysteine, and aspartic proteases are known and can beincluded in a ligand/receptor specificity exchanger.

The section below describes the specificity domains in greater detail.

Specificity Domains

The types of specificity domains that can be used with a ligand/receptorspecificity exchanger are diverse because a vast number of ligands areknown to interact with receptors on bacteria, parasites, fungus, mold,viruses, and cancer cells. Many types of bacteria, parasites, fungus,mold, viruses, and cancer cells, for example, interact withextracellular matrix proteins. Thus, desired specificity domainscomprise at least one ligand that has a peptide sequence that is presentin an extracellular matrix protein. That is, a specificity domain canhave a ligand that has a peptide sequence found in, for example,fibrinogen, collagen, vitronectin, laminin, plasminogen, thrombospondin,and fibronectin.

Investigators have mapped the regions of extracellular matrix proteinsthat interact with several receptors. (See e.g., McDevvit et al., Eur.J. Biochem., 247:416-424 (1997); Flock, Molecular Med. Today, 5:532(1999); and Pei et al., Infect. and Immun. 67:4525 (1999), all of whichare herein expressly incorporated by reference in their entirety). Somereceptors bind to the same region of the extracellular matrix protein,some have overlapping binding domains, and some bind to differentregions altogether. Preferably, the ligands that make up the specificitydomain have an amino acid sequence that has been identified as beinginvolved in adhesion to an extracellular matrix protein. It should beunderstood, however, that random fragments of known ligands for anyreceptor on a pathogen can be used to generate ligand/receptorspecificity exchangers and these candidate ligand/receptor specificityexchangers can be screened in the characterization assays describedinfra to identify the molecules that interact with the receptors on thepathogen.

Some specificity domains have a ligand that interacts with a bacterialadhesion receptor including, but not limited to, extracellularfibrinogen binding protein (Efb), collagen binding protein, vitronectinbinding protein, laminin binding protein, plasminogen binding protein,thrombospondin binding protein, clumping factor A (ClfA), clumpingfactor B (ClfB), fibronectin binding protein, coagulase, andextracellular adherence protein. Ligands that have an amino acidsequence corresponding to the C-terminal portion of the gamma-chain offibrinogen have been shown to competitively inhibit binding offibrinogen to ClfA, a Staphylococcus aureus adhesion receptor. (McDevvitet al., Eur. J. Biochem., 247:416-424 (1997)). Further, Staphylococcusorganisms produce many more adhesion receptors such as Efb, which bindsto the alpha chain fibrinogen, ClfB, which interacts with both the α andβ chain of fibrinogen, and Fbe, which binds to the β chain offibrinogen. (Pei et al., Infect. and Immun. 67:4525 (1999)).Accordingly, preferred specificity domains comprise at least 3 aminoacids of a sequence present in a molecule (e.g., fibrinogen) that canbind to a bacterial adhesion receptor.

Specificity domains can also comprise a ligand that interacts with aviral receptor. Several viral receptors and corresponding ligands areknown and these ligands or fragments thereof can be incorporated into aligand/receptor specificity exchanger. For example, Tong et al., hasidentified an Hepadnavirus receptor, a 170 kd cell surface glycoproteinthat interacts with the pre-S domain of the duck hepatitis B virusenvelope protein (U.S. Pat. No. 5,929,220) and Maddon et al., hasdetermined that the T cell surface protein CD4 (or the soluble formtermedT4) interacts with gp120 of HIV (U.S. Pat. No. 6,093,539); bothreferences are herein expressly incorporated by reference in theirentireties. Thus, specificity domains that interact with a viralreceptor can comprise regions of the pre-S domain of the duck hepatitisB virus envelope protein (e.g., amino acid residues 80-102 or 80-104) orregions of the T cell surface protein CD4 (or the soluble form termedT4)that interacts with gp120 of HIV (e.g., the extracellular domain ofCD4/T4 or fragments thereof). Many more ligands for viral receptorsexist and these molecules or fragments thereof can be used as aspecificity domain.

Specificity domains can also comprise a ligand that interacts with areceptor present on a cancer cell. The proto-oncogene HER-2/neu(C-erbB2) encodes a surface growth factor receptor of the tyrosinekinase family, p185HER2. Twenty to thirty percent of breast cancerpatients over express the gene encoding HER-2/neu (C-erbB2), via geneamplification. Thus, ligand/receptor specificity exchangers comprising aspecificity domain that encodes a ligand for HER-2/neu (C-erbB2) aredesirable embodiments. Many types of cancer cells also over express ordifferentially express integrin receptors. Many preferred embodimentscomprise a specificity domain that interacts with an integrin receptor.Although integrins predominantly interact with extracellular matrixproteins, it is known that these receptors interact with other ligandssuch as invasins, RGD-containing peptides (i.e.,Arginine-Glycine-Aspartate), and chemicals. (See e.g., U.S. Pat. Nos.6,090,944 and 6,090,388; and Brett et al., Eur J. Immunol, 23:1608(1993), all of which are hereby expressly incorporated by reference intheir entireties). Ligands for integrin receptors include, but are notlimited to, molecules that interact with a vitronectin receptor, alaminin receptor, a fibronectin receptor, a collagen receptor, afibrinogen receptor, an α₄β₁ receptor, an α₆β₁ receptor, an α₃β₁receptor, an α₅β₁ receptor, and an α_(v)β₁ receptor. TABLE I also listsseveral preferred specificity domains. The specificity domains describedabove are provided for illustrative purposes only and in no way shouldbe construed to limit the scope of specificity domains that can be usedwith the embodiments described herein.

The next section describes antigenic domains in greater detail.

TABLE I SPECIFICITY DOMAINS YGEGQQHHLGGAKQAGDV (SEQ. ID. No. 1)MSWSLHPRNLILYFYALLFL (SEQ. ID. No. 2) ILYFYALLFLSTCVAYVAT (SEQ. ID. No.3) SSTCVAYVATRDNCCILDER (SEQ. ID. No. 4) RDNCCILDERFGSYCPTTCG (SEQ. ID.No. 5) FGSYCPTTCGIADFLSTYQT (SEQ. ID. No. 6) IADFLSTYQTKVDKDLQSLE (SEQ.ID. No. 7) KVDKDLQSLEDILHQVENKT (SEQ. ID. No. 8) DILHQVENKTSEVKQLIKAI(SEQ. ID. No. 9) SEVKQLIKAIQLTYNPDESS (SEQ. ID. No. 10)QLTYNPDESSKPNMIDAATL (SEQ. ID. No. 11) KPNMIDAATLKSRIMLEEIM (SEQ. ID.No. 12) KSRIMLEEIMKYEASILTHD (SEQ. ID. No. 13) KYEASILTHDSSIRYLQEIY(SEQ. ID. No. 14) SSIRYLQEIYNSNNQKIVNL (SEQ. ID. No. 15)NSNNQKIVNLKEKVAQLEAQ (SEQ. ID. No 16) CQEPCKDTVQIHDITGKDCQ (SEQ. ID. No.17) IHDITGKDCQDIANKGAKQS (SEQ. ID. No. 18) DIANKGAKQSGLYFIKPLKA (SEQ.ID. No. 19) GLYFIKPLKANQQFLVYCEI (SEQ. ID. No. 20) NQQFLVYCEIDGSGNGWTVF(SEQ. ID. No. 21) DGSGNGWTVFQKRLDGSVDF (SEQ. ID. No. 22)QKRLDGSVDFKKNWIQYKEG (SEQ. ID. No. 23) KKNWIQYKEGFGHLSPTGTT (SEQ. ID.No. 24) FGHLSPTGTTEFWLGNEKIH (SEQ. ID. No. 25) EFWLGNEKIHLISTQSAIPY(SEQ. ID. No. 26) LISTQSAIPYALRVELEDWN (SEQ. ID. No. 27)ALRVELEDWNGRTSTADYAM (SEQ. ID. No. 28) GRTSTADYAMFKVGPEADKY (SEQ. ID.No. 29) FKVGPEADKYRLTYAYFAGG (SEQ. ID. No. 30) RLTYAYFAGGDAGDAFDGFD(SEQ. ID. No. 31) DAGDAFDGFDFGDDPSDKFF (SEQ. ID. No. 32)FGDDPSDKFFTSHNGMQFST (SEQ. ID. No. 33) TSHNGMQFSTWDNDNDKFEG (SEQ. ID.No. 34) WDNDNDKFEGNCAEQDGSGW (SEQ. ID. No. 35) NCAEQDGSGWWMNKCHAGHL(SEQ. ID. No. 36) WMNKCHAGHLNGVYYQGGTY (SEQ. ID. No. 37)NGVYYQGGTYSKASTPNGYD (SEQ. ID. No. 38) SKASTPNGYDNGIIWATWKT (SEQ. ID.No. 39) NGIIWATWKTRWYSMKKTTM (SEQ. ID. No. 40) RWYSMKKTTMKIIPFNRLTI(SEQ. ID. No. 41) KIIPFNRLTIGEGQQHHLGGAKQAGDV (SEQ. ID. No. 42)

Antigenic Domains

The diversity of antigenic domains that can be used in theligand/receptor specificity exchangers is also quite large because apathogen or toxin can present many different epitopes. That is, theantigenic domains that can be incorporated into a ligand/receptorspecificity exchanger include epitopes presented by bacteria, fungus,plants, mold, virus, cancer cells, and toxins. Desired antigenic domainscomprise an epitope of a pathogen that already exists in a subject byvirtue of naturally acquired immunity or vaccination. Epitopes ofpathogens that cause childhood diseases, for example, can be used asantigenic domains.

Some embodiments have antigenic domains that interact with an antibodythat has been administered to the subject. For example, an antibody thatinteracts with an antigenic domain on a specificity exchanger can beco-administered with the specificity exchanger. Further, an antibodythat interacts with a ligand/receptor specificity exchanger may notnormally exist in a subject but the subject has acquired the antibody byintroduction of a biologic material (e.g., serum, blood, or tissue). Forexample, subjects that undergo blood transfusion acquire numerousantibodies, some of which can interact with an antigenic domain of aligand/receptor specificity exchanger. Some preferred antigenic domainsfor use in a ligand/receptor specificity exchanger comprise viralepitopes including, but not limited to, the herpes simplex virus,hepatitis B virus, TT virus, and the poliovirus.

In some embodiments, it is also preferred that the antigenic domainscomprise an epitope of a pathogen or toxin that is recognized by a“high-titer antibody”. Approaches to determine whether the epitope of apathogen or toxin is recognizable by a high titer antibody are providedinfra. Epitopes of a pathogen that can be included in an antigenicdomain of a ligand/receptor specificity exchanger include epitopes onpeptide sequences disclosed in Swedish Pat No. 9901601-6; U.S. Pat. No.5,869,232; Mol. Immunol. 28: 719-726 (1991); and J. Med. Virol.33:248-252 (1991); all references are herein expressly incorporated byreference in their entireties. TABLE II provides the amino acid sequenceof several preferred antigenic domains.

The section following TABLE II, describes the preparation ofligand/receptor specificity exchangers in greater detail.

TABLE II ANTIGENIC DOMAINS GLYSSIWLSPGRSYFET (SEQ. ID. No. 43)YTDIKYNPFTDRGEGNM (SEQ. ID. No. 44) DQNIHMNARLLIRSPFT (SEQ. ID. No. 45)LIRSPFTDPQLLVHTDP (SEQ. ID. No. 46) QKESLLFPPVKLLRRVP (SEQ. ID. No. 47)PALTAVETGAT (SEQ. ID. No. 48) STLVPETT (SEQ. ID. No. 49) TPPAYRPPNAPIL(SEQ. ID. No. 50) EIPALTAVE (SEQ. ID. No. 51) LEDPASRDLV (SEQ. ID. No.52) HRGGPEEF (SEQ. ID. No. 53) HRGGPEE (SEQ. ID. No. 54)VLICGENTVSRNYATHS (SEQ. ID. No. 55) KINTMPPFLDTELTAPS (SEQ. ID. No. 56)PDEKSQREILLNKIASY (SEQ. ID. No. 57) TATTTTYAYPGTNRPPV (SEQ. ID. No. 58)STPLPETT (SEQ. ID. No. 59)

Methods of Making Ligand/Receptor Specificity Exchangers that Interactwith Receptors on Bacteria, Parasites, Fungus, Mold, Viruses, and CancerCells

In some embodiments, the specificity and antigenic domains are madeseparately and are subsequently joined together (e.g., through linkersor by association with a common carrier molecule) and in otherembodiments, the specificity domain and antigenic domain are made aspart of the same molecule. For example, any of the specificity domainslisted in TABLE I can be joined to any of the antigenic domains of TABLEII. Although the specificity and antigenic domains could be madeseparately and joined together through a linker or carrier molecule(e.g., a complex comprising a biotinylated specificity domain,streptavidin, and a biotinylated antigenic domain), it is preferred thatthe ligand/receptor specificity exchanger is made as a fusion protein.Thus, preferred embodiments include fusion proteins comprising any ofthe specificity domains listed in TABLE I joined to any of the antigenicdomains of TABLE II.

Ligand/receptor specificity exchangers can be generated in accordancewith conventional methods of protein engineering, protein chemistry,organic chemistry, and molecular biology. Additionally, some commercialenterprises manufacture made-to-order peptides and a ligand/receptorspecificity exchanger can be obtained by providing such a company withthe sequence of a desired ligand/receptor specificity exchanger andemploying their service to manufacture the agent according to particularspecifications (e.g., Bachem AG, Switzerland). Preferably, theligand/receptor specificity exchangers are prepared by chemicalsynthesis methods (such as solid phase peptide synthesis) usingtechniques known in the art, such as those set forth by Merrifield etal., J. Am. Chem. Soc. 85:2149 (1964), Houghten et al., Proc. Natl.Acad. Sci. USA, 82:51:32 (1985), Stewart and Young (Solid phase peptidesynthesis, Pierce Chem Co., Rockford, Ill. (1984), and Creighton, 1983,Proteins: Structures and Molecular Principles, W. H. Freeman & Co.,N.Y.; all references are herein expressly incorporated by reference intheir entireties.

By one approach, solid phase peptide synthesis is performed using anApplied Biosystems 430A peptide synthesizer (Applied Biosystems, FosterCity, Calif.). Each synthesis uses a p-methylbenzylhydrylamine solidphase support resin (Peptide International, Louisville, Ky.) yielding acarboxyl terminal amide when the peptides are cleaved off from the solidsupport by acid hydrolysis. Prior to use, the carboxyl terminal amidecan be removed and the ligand/receptor specificity exchangers can bepurified by high performance liquid chromatography (e.g., reverse phasehigh performance liquid chromatography (RP-HPLC) using a PepS-15 C18column (Pharmacia, Uppsala, Sweden)) and sequenced on an AppliedBiosystems 473A peptide sequencer. An alternative synthetic approachuses an automated peptide synthesizer (Syro, Multisyntech, Tubingen,Germany) and 9-fluorenylmethoxycarbonyl (fmoc) protected amino acids(Milligen, Bedford, Mass.).

While the ligand/receptor specificity exchangers can be chemicallysynthesized, it can be more efficient to produce these polypeptides byrecombinant DNA technology using techniques well known in the art. Suchmethods can be used to construct expression vectors containingnucleotide sequences encoding a ligand/receptor specificity exchangerand appropriate transcriptional and translational control signals. Thesemethods include, for example, in vitro recombinant DNA techniques,synthetic techniques, and in vivo genetic recombination. Alternatively,RNA capable of encoding a ligand/receptor specificity exchanger can bechemically synthesized using, for example, synthesizers. See, forexample, the techniques described in Oligonucleotide Synthesis, 1984,Gait, M. J. ed., IRL Press, Oxford, which is incorporated by referenceherein in its entirety.

A variety of host-expression vector systems can be utilized to expressthe ligand/receptor specificity exchangers. Where the ligand/receptorspecificity exchanger is a soluble molecule it can be recovered from theculture, i.e., from the host cell in cases where the peptide orpolypeptide is not secreted, and from the culture media in cases wherethe peptide or polypeptide is secreted by the cells. However, theexpression systems also encompass engineered host cells that expressmembrane bound ligand/receptor specificity exchangers. Purification orenrichment of the ligand/receptor specificity exchangers from suchexpression systems can be accomplished using appropriate detergents andlipid micelles and methods well known to those skilled in the art.

The expression systems that can be used include, but are not limited to,microorganisms such as bacteria (e.g., E. coli or B. subtilis)transformed with recombinant bacteriophage DNA, plasmid DNA or cosmidDNA expression vectors containing nucleotide sequences encoding aligand/receptor specificity exchanger; yeast (e.g., Saccharomyces,Pichia) transformed with recombinant yeast expression vectors containingnucleotide sequences encoding ligand/receptor specificity exchangers;insect cell systems infected with recombinant virus expression vectors(e.g., Baculovirus) containing nucleic acids encoding theligand/receptor specificity exchangers; or mammalian cell systems (e.g.,COS, CHO, BHK, 293, 3T3) harboring recombinant expression constructscontaining nucleic acids encoding ligand/receptor specificityexchangers.

In bacterial systems, a number of expression vectors can beadvantageously selected depending upon the use intended for theligand/receptor specificity exchanger. For example, when a largequantity is desired (e.g., for the generation of pharmaceuticalcompositions of ligand/receptor specificity exchangers) vectors thatdirect the expression of high levels of fusion protein products that arereadily purified can be desirable. Such vectors include, but are notlimited, to the E. coli expression vector pUR278 (Ruther et al., EMBOJ., 2:1791 (1983), in which the ligand/receptor specificity exchangercoding sequence can be ligated individually into the vector in framewith the lacZ coding region so that a fusion protein is produced; pINvectors (Inouye & Inouye, Nucleic Acids Res., 13:3101-3109 (1985); VanHeeke & Schuster, J. Biol. Chem., 264:5503-5509 (1989)); and the like.pGEX vectors can also be used to express foreign polypeptides as fusionproteins with glutathione S-transferase (GST). In general, such fusionproteins are soluble and can be purified from lysed cells by adsorptionto glutathione-agarose beads followed by elution in the presence of freeglutathione. The PGEX vectors are designed to include thrombin or factorXa protease cleavage sites so that the cloned target gene product can bereleased from the GST moiety.

In an insect system, Autographa californica nuclear polyhedrosis virus(AcNPV) is used as a vector to express foreign genes. The virus grows inSpodoptera frugiperda cells. The ligand/receptor specificity exchangergene coding sequence can be cloned individually into non-essentialregions (for example the polyhedrin gene) of the virus and placed undercontrol of an AcNPV promoter (for example the polyhedrin promoter).Successful insertion of ligand/receptor specificity exchanger genecoding sequence will result in inactivation of the polyhedrin gene andproduction of non-occluded recombinant virus, (i.e., virus lacking theproteinaceous coat coded for by the polyhedrin gene). These recombinantviruses are then used to infect Spodoptera frugiperda cells in which theinserted gene is expressed. (E.g., see Smith et al., J. Virol. 46: 584(1983); and Smith, U.S. Pat. No. 4,215,051).

In mammalian host cells, a number of viral-based expression systems canbe utilized. In cases where an adenovirus is used as an expressionvector, a nucleic acid sequence encoding a ligand/receptor specificityexchanger can be ligated to an adenovirus transcription/translationcontrol complex, e.g., the late promoter and tripartite leader sequence.This chimeric gene can then be inserted in the adenovirus genome by invitro or in vivo recombination. Insertion in a non-essential region ofthe viral genome (e.g., region E1 or E3) will result in a recombinantvirus that is viable and capable of expressing the ligand/receptorspecificity exchanger gene product in infected hosts. (See e.g., Logan &Shenk, Proc. Natl. Acad. Sci. USA 81:3655-3659 (1984)). Specificinitiation signals can also be required for efficient translation ofinserted ligand/receptor specificity exchanger nucleotide sequences(e.g., the ATG initiation codon and adjacent sequences). In most cases,an exogenous translational control signal, including, perhaps, the ATGinitiation codon, should be provided. Furthermore, the initiation codonshould be in phase with the reading frame of the desired coding sequenceto ensure translation of the entire insert. These exogenoustranslational control signals and initiation codons can be of a varietyof origins, both natural and synthetic. The efficiency of expression canalso be enhanced by the inclusion of appropriate transcription enhancerelements, transcription terminators, etc. (See Bittner et al., Methodsin Enzymol., 153:516-544 (1987)).

In addition, a host cell strain can be chosen that modulates theexpression of the inserted sequences, or modifies and processes the geneproduct in the specific fashion desired. Such modifications (e.g.,glycosylation) and processing (e.g., cleavage) of protein products canbe important for some embodiments. Different host cells havecharacteristic and specific mechanisms for the post-translationalprocessing and modification of proteins and gene products. Appropriatecell lines or host systems can be chosen to ensure the correctmodification and processing of the foreign protein expressed. To thisend, eukaryotic host cells that possess the cellular machinery forproper processing of the primary transcript, glycosylation, andphosphorylation of the gene product can be used. Such mammalian hostcells include, but are not limited to, CHO, VERO, BHK, HeLa, COS, MDCK,293, 3T3, and WI38.

For long-term, high-yield production of recombinant proteins, stableexpression is preferred. For example, cell lines that stably express theligand/receptor specificity exchangers described above can beengineered. Rather than using expression vectors that contain viralorigins of replication, host cells can be transformed with DNAcontrolled by appropriate expression control elements (e.g., promoter,enhancer sequences, transcription terminators, polyadenylation sites,etc.), and a selectable marker. Following the introduction of theforeign DNA, engineered cells are allowed to grow for 1-2 days in anenriched media, and then are switched to a selective media. Theselectable marker in the recombinant plasmid confers resistance to theselection and allows cells to stably integrate the plasmid into theirchromosomes and grow to form foci which in turn are cloned and expandedinto cell lines. This method is advantageously used to engineer celllines which express a ligand/receptor specificity exchanger.

A number of selection systems can be used, including but not limited tothe herpes simplex virus thymidine kinase (Wigler, et al., Cell 11:223(1977)), hypoxanthine-guanine phosphoribosyltransferase (Szybalska &Szybalski, Proc. Natl. Acad. Sci. USA 48:2026 (1962)), and adeninephosphoribosyltransferase (Lowy, et al., Cell 22:817 (1980)) genes canbe employed in tk.sup.-, hgprt.sup.- or aprt.sup.-cells, respectively.Also, antimetabolite resistance can be used as the basis of selectionfor the following genes: dhfr, which confers resistance to methotrexate(Wigler, et al., Proc. Natl. Acad. Sci. USA 77:3567 (1980)); O'Hare, etal., Proc. Natl. Acad. Sci. USA 78:1527 (1981)); gpt, which confersresistance to mycophenolic acid (Mulligan & Berg, Proc. Natl. Acad. Sci.USA 78:2072 (1981)); neo, which confers resistance to the aminoglycosideG-418 (Colberre-Garapin, et al., J. Mol. Biol. 150:1 (1981)); and hygro,which confers resistance to hygromycin (Santerre, et al., Gene 30:147(1984)).

The following section describes the ligand/receptor specificityexchanger characterization assays in greater detail.

Ligand/receptor Specificity Exchanger Characterization Assays

Preferably, ligand/receptor specificity exchangers are analyzed fortheir ability to interact with a receptor and/or the ability to interactwith an antibody that may be present in a subject. The term“characterization assay” refers to an assay, experiment, or analysismade on a ligand/receptor specificity exchanger, which evaluates theability of a ligand/receptor specificity exchanger to interact with areceptor (e.g., a surface receptor present in bacteria, virus, mold, orfungi) or an antibody (e.g., an antibody that recognizes an epitopefound on a pathogen), or effect the proliferation of a pathogen.Encompassed by the term “characterization assay” are binding studies(e.g., enzyme immunoassays (EIA), enzyme-linked immunoassays (ELISA),competitive binding assays, computer generated binding assays, supportbound binding studies, and one and two hybrid systems), and infectivitystudies (e.g., reduction of viral infection, propagation, and attachmentto a host cell).

Preferred binding assays use multimeric agents. One form of multimericagent concerns a composition comprising a ligand/receptor specificityexchanger, or fragments thereof disposed on a support. Another form ofmultimeric agent involves a composition comprising a receptor or anantibody specific for the antigenic domain of a ligand/receptorspecificity exchanger disposed on a support. A “support” can be acarrier, a protein, a resin, a cell membrane, or any macromolecularstructure used to join or immobilize such molecules. Solid supportsinclude, but are not limited to, the walls of wells of a reaction tray,test tubes, polystyrene beads, magnetic beads, nitrocellulose strips,membranes, microparticles such as latex particles, animal cells,Duracyte®, artificial cells, and others. A ligand/receptor specificityexchanger can also be joined to inorganic supports, such as siliconoxide material (e.g. silica gel, zeolite, diatomaceous earth or aminatedglass) by, for example, a covalent linkage through a hydroxy, carboxy,or amino group and a reactive group on the support.

In some multimeric agents, the macromolecular support has a hydrophobicsurface that interacts with a portion of the ligand/receptor specificityexchanger, receptor or ligand by a hydrophobic non-covalent interaction.In some cases, the hydrophobic surface of the support is a polymer suchas plastic or any other polymer in which hydrophobic groups have beenlinked such as polystyrene, polyethylene or polyvinyl. Additionally, aligand/receptor specificity exchanger, receptor or an antibody specificfor the antigenic domain of a ligand/receptor specificity exchanger canbe covalently bound to supports including proteins andoligo/polysaccarides (e.g. cellulose, starch, glycogen, chitosane oraminated sepharose). In these later multimeric agents, a reactive groupon the molecule, such as a hydroxy or an amino group, is used to join toa reactive group on the carrier so as to create the covalent bond.Additional multimeric agents comprise a support that has other reactivegroups that are chemically activated so as to attach the ligand/receptorspecificity exchanger, receptor, or antibody specific for the antigenicdomain of a ligand/receptor specificity exchanger. For example, cyanogenbromide activated matrices, epoxy activated matrices, thio andthiopropyl gels, nitrophenyl chloroformate and N-hydroxy succinimidechlorformate linkages, or oxirane acrylic supports can be used. (Sigma).Furthermore, in some embodiments, a liposome or lipid bilayer (naturalor synthetic) is contemplated as a support and a ligand/receptorspecificity exchanger, receptor, or an antibody specific for theantigenic domain of a ligand/receptor specificity exchanger can beattached to the membrane surface or are incorporated into the membraneby techniques in liposome engineering. By one approach, liposomemultimeric supports comprise a ligand/receptor specificity exchanger,receptor, or an antibody specific for the antigenic domain of aligand/receptor specificity exchanger that is exposed on the surface.

The insertion of linkers (e.g., “λ linkers” engineered to resemble theflexible regions of λ phage) of an appropriate length between theligand/receptor specificity exchanger, receptor, or antibody specificfor the antigenic domain of a ligand/receptor specificity exchanger andthe support are also contemplated so as to encourage greater flexibilityand overcome any steric hindrance that can be presented by the support.The determination of an appropriate length of linker that allows foroptimal binding can be found by screening the attached molecule withvarying linkers in the characterization assays detailed herein.

Several approaches to characterize ligand/receptor specificityexchangers employ a multimeric described above. For example,support-bound ligand/receptor specificity exchanger can be contactedwith “free” adhesion receptors and an association can be determineddirectly (e.g., by using labeled adhesion receptors) or indirectly(e.g., by using a labeled ligand directed to an adhesion receptor).Thus, candidate ligand/receptor specificity exchangers are identified asbona fide ligand/receptor specificity exchangers by virtue of theassociation of the receptors with the support-bound candidateligand/receptor specificity exchanger. Alternatively, support-boundadhesion receptors can be contacted with “free” ligand/receptorspecificity exchangers and the amount of associated ligand/receptorspecificity exchanger can be determined directly (e.g., by using labeledligand/receptor specificity exchanger) or indirectly (e.g., by using alabeled antibody directed to the antigenic domain of the ligand/receptorspecificity exchanger). Similarly, by using an antibody specific for theantigenic domain of a ligand/receptor specificity exchanger disposed ona support and labeled ligand/receptor specificity exchanger (or asecondary detection reagent, e.g., a labeled receptor or antibody to theligand/receptor specificity exchanger) the ability of the antibody tobind to the antigenic domain of the ligand/receptor specificityexchanger can be determined.

Some characterization assays evaluate the ability of the ligand/receptorspecificity exchanger to interact with the target receptor and theredirecting antibody while other characterization assays are designed todetermine whether a ligand/receptor specificity exchanger can bind toboth the target receptor and the redirecting antibody. In general, thecharacterization assays can be classified as: (1) in vitrocharacterization assays, (2) cellular characterization assays, and (3)in vivo characterization assays.

A discussion of each type of characterization assay is provided in thefollowing sections.

In Vitro Characterization Assays

There are many types of in vitro assays that can be used to determinewhether a ligand/receptor specificity exchanger binds to a particularreceptor and whether an antibody found in a subject can bind to theligand/receptor specificity exchanger. Most simply, the receptor isbound to a support (e.g., a petri dish) and the association of theligand/receptor specificity exchanger with the receptor is monitoreddirectly or indirectly, as described above. Similarly, a primaryantibody directed to the antigenic domain of a ligand/receptorspecificity exchanger (e.g., an antibody found in a subject) can bebound to a support and the association of a ligand/receptor specificityexchanger with the primary antibody can be determined directly (e.g.,using labeled ligandireceptor specificity exchanger) or indirectly(e.g., using labeled receptor or a labeled secondary antibody thatinteracts with an epitope on the ligand/receptor specificity exchangerthat does not compete with the epitope recognized by the primaryantibody).

Another approach involves a sandwich-type assay, wherein the receptor isbound to a support, the ligand/receptor specificity exchanger is boundto the receptor, and the primary antibody is bound to theligand/receptor specificity exchanger. If labeled primary antibody isused, the presence of a receptor/specificity exchanger/primary antibodycomplex can be directly determined. The presence of thereceptor/specificity exchanger/primary antibody complex can also bedetermined indirectly by using, for example, a labeled secondaryantibody that reacts with the primary antibody at an epitope that doesnot interfere with the binding of the primary antibody to theligand/receptor specificity exchanger. In some cases, it may be desiredto use a labeled tertiary antibody to react with an unlabeled secondaryantibody, thus, forming a receptor/specificity exchanger/primaryantibody/secondary antibody/labeled tertiary antibody complex.

The example below describes a characterization assay that was performedto determine whether a ligand/receptor specificity exchanger interactswith bacteria having the ClfA receptor.

EXAMPLE 1

Ligand/receptor specificity exchangers having specificity domains(approximately 20 amino acids long) corresponding to various regions ofthe fibrinogen gamma-chain sequence were produced using standardtechniques in peptide synthesis using fmoc chemistry (Syro,MultiSynTech, Germany) and these ligand/receptor specificity exchangerswere analyzed for their ability to bind the ClfA receptor and anantibody specific for their antigenic domains. The sequences of theseligand/receptor specificity exchangers are listed in TABLE III and areprovided in the Sequence listing (SEQ. ID. Nos. 60-103). Theligand/receptor specificity exchangers used in this analysis have anantigenic domain that presents an epitope of herpes simplex virus gG2protein, which is recognized by a monoclonal antibody for herpes simplexvirus gG2 proteins. Serial dilutions of these ligand/receptorspecificity exchangers were made in phosphate buffered saline (PBS)containing 2 μg/ml goat serum. (Sigma Chemicals, St. Louis, Mo.) and0.5% Tween 20 (PBS-GT). The receptor ClfA was passively adsorbed at 10μg/ml to 96 well microtiter plates in 50 mM sodium carbonate buffer, pH9.6, overnight at +4° C.

The diluted ligand/receptor specificity exchangers were then incubatedon the plates for 60 minutes. The ability of the ligand/receptorspecificity exchanger to interact with the receptor was determined byapplying a primary antibody to the plate and incubating for 60 minutes(a 1:1000 dilution of mAb for herpes simplex virus gG2 proteins). Thebound primary mAb was then indicated by a rabbit anti-mouse IgG (Sigma)secondary antibody and a peroxidase labeled goat anti-rabbit IgG (Sigma)tertiary antibody. The plates were developed by incubation withdinitro-phenylene-diamine (Sigma) and the absorbance at 405 nm wasanalyzed.

Every ligand-/receptor specificity exchanger provided in TABLE III (SEQ.ID Nos. 60-103) appreciably bound the immobilized ClfA and also allowedfor the binding of the mAb specific for HSV gG2 protein. The methoddescribed above for determining the affinity of a ligand/receptorspecificity exchanger for an adhesion receptor and a primary antibodycan be performed for any candidate ligand/receptor specificity exchangercomprising any specificity domain and any antigenic domain provided thatthe appropriate sequences and adhesion receptors are used.

The example following TABLE III describes several cellular-basedcharacterization assays that can be performed to determine whether aligand/receptor specificity exchanger has an effect on the proliferationof a pathogen.

TABLE III LIGAND/RECEPTOR SPECIFICITY EXCHANGERS YGEGQQHHLGGAKQAGDVHRGGPEEF (SEQ. ID. No. 60) YGEGQQHHLGGAKQAGDVHRGGPEE (SEQ. ID. No. 61)YGEGQQHHLGGAKQAGDVSTPLPETT (SEQ. ID. No. 62) MSWSLHPRNLILYFYALLFLHRGGPEE(SEQ. ID. No. 63) ILYFYALLFLSTCVAYVATHRGGPEE (SEQ. ID. No. 64)SSTCVAYVATRDNCCILDERHRGGPEE (SEQ. ID. No. 65)RDNCCILDERFGSYCPTTCGHRGGPEE (SEQ. ID. No. 66)FGSYCPTTCGIADFLSTYQTHRGGPEE (SEQ. ID. No. 67)IADFLSTYQTKVDKDLQSLEHRGGPEE (SEQ. ID. No. 68)KVDKDLQSLEDILHQVENKTHRGGPEE (SEQ. ID. No. 69)DILHQVENKTSEVKQLIKAIHRGGPEE (SEQ. ID. No. 70)SEVKQLIKAIQLTYNPDESSHRGGPEE (SEQ. ID. No. 71)QLTYNPDESSKPNMIDAATLHRGGPEE (SEQ. ID. No. 72)KPNMIDAATLKSRIMLEEIMHRGGPEE (SEQ. ID. No. 73)KSRIMLEEIMKYEASILTHDHRGGPEE (SEQ. ID. No. 74)KYEASILTHDSSIRYLQEIYHRGGPEE (SEQ. ID. No. 75)SSIRYLQEIYNSNNQKIVNLHRGGPEE (SEQ. ID. No. 76)NSNNQKIVNLKEKVAQLEAQHRGGPEE (SEQ. ID. No. 77)CQEPCKDTVQIHDITGKDCQHRGGPEE (SEQ. ID. No. 78)IHDITGKDCQDIANKGAKQSHRGGPEE (SEQ. ID. No. 79)DIANKGAKQSGLYFIKPLKAHRGGPEE (SEQ. ID. No. 80)GLYFIKPLKANQQFLVYCEIHRGGPEE (SEQ. ID. No. 81)NQQFLVYCEIDGSGNGWTVFHRGGPEE (SEQ. ID. No. 82)DGSGNGWTVFQKRLDGSVDFHRGGPEE (SEQ. ID. No. 83)QKRLDGSVDFKKNWIQYKEGHRGGPEE (SEQ. ID. No. 84)KKNWIQYKEGFGHLSPTGTTHRGGPEE (SEQ. ID. No. 85)FGHLSPTGTTEFWLGNEKIHHRGGPEE (SEQ. ID. No. 86)EFWLGNEKIHLISTQSAIPYHRGGPEE (SEQ. ID. No. 87)LISTQSAIPYALRVELEDWNHRGGPEE (SEQ. ID. No. 88)ALRVELEDWNGRTSTADYAMHRGGPEE (SEQ. ID. No. 89)GRTSTADYAMFKVGPEADKYHRGGPEE (SEQ. ID. No. 90)FKVGPEADKYRLTYAYFAGGHRGGPEE (SEQ. ID. No. 91)RLTYAYFAGGDAGDAFDGFDHRGGPEE (SEQ. ID. No. 92)DAGDAFDGFDFGDDPSDKFFHRGGPEE (SEQ. ID. No. 93)FGDDPSDKFFTSHNGMQFSTHRGGPEE (SEQ. ID. No. 94)TSHNGMQFSTWDNDNDKFEGHRGGPEE (SEQ. ID. No. 95)WDNDNDKFEGNCAEQDGSGWHRGGPEE (SEQ. ID. No. 96)NCAEQDGSGWWMNKCHAGHLHRGGPEE (SEQ. ID. No. 97)WMNKCHAGHLNGVYYQGGTYHRGGPEE (SEQ. ID. No. 98)NGVYYQGGTYSKASTPNGYDHRGGPEE (SEQ. ID. No. 99)SKASTPNGYDNGIIWATWKTHRGGPEE (SEQ. ID. No. 100)NGIIWATWKTRWYSMKKTTMHRGGPEE (SEQ. ID. No. 101)RWYSMKKTTMKIIPFNRLTIHRGGPEE (SEQ. ID. No. 102)KIIPFNRLTIGEGQQHHLGGAKQAGDVHRGGPEE (SEQ. ID. No. 103)

Pathogen-based Characterization Assays

In another type of characterization assay, a pathogen-based approach isused to evaluate the ability of a ligand/receptor specificity exchangerto interact with a pathogen and an antibody directed to the antigenicdomain of the ligand/receptor specificity exchanger. This analysis alsoreveals the ability of the ligand/receptor specificity exchanger toeffect proliferation of a pathogen because, in the body of a subject,the interaction of the ligand/receptor specificity exchanger with apathogen and an antibody directed to the antigenic domain of theligand/receptor specificity exchanger is followed by humoral andcellular responses that purge the pathogen from the subject (e.g.,complement fixation and macrophage degradation). In general, thepathogen-based characterization assays involve providing ligand/receptorspecificity exchangers to cultured pathogens and monitoring theassociation of the ligand/receptor specificity exchanger with the cellsor virus. Several types of pathogen-based characterization assays can beused and the example below describes some of the preferredcharacterization assays in greater detail.

EXAMPLE 2

One type of pathogen-based characterization assay involves binding of aligand/receptor specificity exchanger to bacteria disposed on a support.Accordingly, bacteria that produce Clfa (e.g., Staphylococcus aureus, orEscherichia coli.) are grown in culture or on a agar plate in a suitablegrowth media (e.g., LB broth, blood broth, LB agar or blood agar). Thecells are then transferred to a membrane (e.g., nitrocellulose or nylon)by either placing the culture on the membrane under vacuum (e.g., usinga dot-blot manifold apparatus) or by placing the membrane on thecolonies for a time sufficient to permit transfer. The cells that arebound to the membrane are then provided a serial dilution of aligand/receptor specificity exchanger (e.g., 500 ng, 1 μg, 5 μg, 10 μg,25 μg, and 50 μg of ligand/receptor specificity exchanger in a totalvolume of 2001 μl of PBS). In one experiment, the ligand/receptorspecificity exchangers listed in TABLE III are used. The dilutedligand/receptor specificity exchangers are then incubated on themembranes for 60 minutes. Subsequently, the non-bound ligand/receptorspecificity exchangers are removed and the membrane is washed with PBS(e.g., 3 washes with 2 ml of PBS per wash). Next, a 1:100-1:1000dilution of a primary antibody that interacts with the antigenic domainof the ligand/receptor specificity exchanger (e.g., mAb for herpessimplex virus gG2 protein) is provided and the binding reaction isallowed to occur for 60 minutes. Again, the membrane is washed with PBS(e.g., 3 washes with 2 ml of PBS per wash) to remove unbound primaryantibody. Appropriate controls include the membrane itself, bacteria onthe membrane without a ligand/receptor specificity exchanger, andbacteria on the membrane with ligand/receptor specificity exchanger butno primary antibody.

To detect the amount of ligand/receptor specificity exchanger bound tothe bacteria on the membrane, a secondary antibody (e.g., rabbitanti-mouse IgG (Sigma)) and a tertiary antibody (e.g., a peroxidaselabeled goat anti-rabbit IgG (Sigma)) are used. Of course, a labeledsecondary antibody that interacts with the primary antibody can be usedas well. As above, the secondary antibody is contacted with the membranefor 60 minutes and the non-bound secondary antibody is washed from themembrane with PBS (e.g., 3 washes with 2 ml of PBS per wash). Then, thetertiary antibody is contacted with the membrane for 60 minutes and thenon-bound tertiary antibody is washed from the membrane with PBS (e.g.,3 washes with 2 ml of PBS per wash). The bound tertiary antibody can bedetected by incubating the membrane with dinitro-phenylene-diamine(Sigma).

Another approach involves the use of an immobilized ligand/receptorspecificity exchanger. Accordingly, primary antibody (e.g., mAb forherpes simplex virus gG2 protein) is bound to a petri dish. Once theprimary antibody is bound, various dilutions of a ligand/receptorspecificity exchanger (e.g., a ligand/receptor specificity exchangerprovided in TABLE III) are added to the coated dish. The ligand/receptorspecificity exchanger is allowed to associate with the primary antibodyfor 60 minutes and the non-bound ligand/receptor specificity exchangeris washed away (e.g., three washes with 2 ml of PBS). Appropriatecontrols include petri dishes without primary antibody orligand/receptor specificity exchanger.

Subsequently, a turbid solution of bacteria (e.g., E. coli) are added tothe petri dishes and the bacteria are allowed to interact with theimmobilized ligand/receptor specificity exchanger for 60 minutes. Thenon-bound bacteria are then removed by washing with PBS (e.g., 3 washeswith 2 ml of PBS). Next, growth media (e.g., LB broth) is added to thepetri dish and the culture is incubated overnight. Alternatively, LBagar is added to the petri dish and the culture is incubated overnight.An interaction between the ligand/receptor specificity exchanger and thebacteria can be observed visually (e.g., turbid growth media, which canbe quantified using spectrophotometric analysis or the appearance ofcolonies on the agar).

By modifying the approaches described above, one of skill in the art canevaluate the ability of a ligand/receptor specificity exchanger tointeract with a virus. For example, soluble fragments of T4 glycoproteinhave been shown to interact with a human immunodeficiency virus (HIV)envelope glycoprotein. (See e.g., U.S. Pat. No. 6,093,539, hereinexpressly incorporated by reference in its entirety). Ligand/receptorspecificity exchangers having a specificity domain comprising a fragmentof T4 glycoprotein that interacts with HIV envelope glycoprotein (e.g.,amino acids 1-419 of the T4 glycoprotein sequence provided in U.S. Pat.No. 6,093,539 or a portion thereof) can be made by synthesizing a fusionprotein having the specificity-domain joined to an antigenic domain(e.g., an antigenic domain listed in TABLE II). Although peptidechemistry can be used to make the ligand/receptor specificity exchanger,it is preferred that an expression construct having the fragment of T4glycoprotein joined to an antigenic domain is made and transfected intoa suitable cell. The expression and purification strategies described inU.S. Pat. No. 6,093,539 and above can also be employed.

Once the ligand/receptor specificity exchanger has been constructed afilter binding assay is performed. Accordingly, serial ten-folddilutions of HIV inoculum are applied to a membrane (e.g. nitrocelluloseor nylon) in a dot blot apparatus under constant vacuum. Then serial tenfold dilutions of the ligand/receptor specificity exchanger are appliedto the bound HIV particles. The ligand/receptor specificity exchanger iscontacted with the particles for 60 minutes before applying vacuum andwashing with PBS (e.g., 3 washes with 2 ml of PBS per wash)). Once thenon-bound ligand/receptor specificity exchanger is removed, ten foldserial dilutions of the primary antibody, which binds to the antigenicdomain, are added to the samples and the binding reaction is allowed tooccur for 60 minutes. Then a vacuum is applied and the non-bound primaryantibody is washed with PBS (e.g., 3 washes with 2 ml of PBS per wash)).The detection of the bound primary antibody can be accomplished, asdescribed above.

The ability of a ligand/receptor specificity exchanger to interact witha virus can also be evaluated in a sandwich-type assay. Accordingly, aprimary antibody that interacts with the antigenic domain of theligand/receptor specificity exchanger is immobilized in micro titerwells and serial dilutions of ligand/receptor specificity exchanger areadded to the primary antibody so as to create a primaryantibody/specificity exchanger complex, as described above. Next, tenfold serial dilutions of HIV inoculum are added and the binding reactionis allowed to occur for 60 minutes. Non-bound HIV particles are removedby successive washes in PBS. Detection of the bound HIV particles can beaccomplished using a radiolabeled anti-HIV antibody (e.g., antibodyobtained from sera from a person suffering with HIV infection).

While the examples above describe pathogen-based assays using bacteriaand a virus, modifications of these approaches can be made to study theinteraction of ligand/receptor specificity exchangers with mammaliancells. For example, the ability of a ligand/receptor specificityexchanger to interact with an integrin receptor present on a cancer cellcan be determined as follows. Melanoma cells that express an α_(v)β₃receptor (e.g., M21 human melanoma cells) bind fibrinogen and thisinteraction can be blocked by administering an RGD containing peptide(See e.g., Katada et al., J. Biol. Chem. 272: 7720 (1997) andFelding-Haberrnann et al., J. Biol. Chem. 271:5892-5900 (1996); bothreferences herein expressly incorporated by reference in theirentireties). Similarly, many other types of cancer cells expressintegrins that interact with RGD peptides. By one approach, cancer cellsthat expresses an RGD-responsive integrin (e.g., M21 human melanomacells) are cultured to confluency. M21 cells can be grown in DMEM mediawith 10% fetal bovine serum, 20 mM Hepes, and 1 mM pyruvate.

Preferably, the cells are stained with hydroethidine (Polysciences,Inc., Warrington, Pa.) at 20 μg/ml final concentration (2×10⁶ cells/ml)for 30 min at 37° C. and then washed twice to remove excess dye.Hydroethidine intercalates into the DNA resulting in a red fluorescentlabeling of the cells and does not impair the cell's adhesive functions.The staining provides a way to quantify the binding of a ligand/receptorspecificity exchanger to the cells. That is, the total number ofhydroethidine stained cells can be compared to the number of cells boundto a fluorescently labeled primary antibody/specificity exchangercomplex so as to determine the binding efficiency.

Accordingly, the stained cells are incubated with various dilutions of aligand/receptor specificity exchanger comprising a RGD sequence (e.g.,GRGDSPHRGGPEE (SEQ. ID No. 104) or WSRGDWHRGGPEE (SEQ. ID No. 105)).After a 60 minute incubation, the non-bound ligand/receptor specificityexchanger is removed by several washes in DMEM media with 10% fetalbovine serum, 20 mM Hepes, and 1 mM pyruvate (e.g., 3 washes of 5 ml ofmedia). Next, a 1:100 -1:1000 dilution of a primary antibody thatinteracts with the antigenic domain of the ligand/receptor specificityexchanger (e.g., mAb for herpes simplex virus gG2 protein) is providedand the binding reaction is allowed to occur for 60 minutes.Subsequently, several washes in media are performed to remove anynon-bound primary antibody. Appropriate controls include stained cellswithout ligand/receptor specificity exchanger or stained cells withoutprimary antibody.

Following binding of the primary antibody, a goat anti-mouse FITClabeled antibody (1:100 dilution) (Sigma) is added and binding isallowed to occur for 60 minutes. Again, several media washes are made toremove any non-bound secondary antibody. Analysis is made by flowcytometry with filter settings at 543/590 nm for hydroethidine and495/525 nm for fluorescin. One will observe an appreciable binding ofprimary antibody to the ligand/receptor specificity exchanger/cellcomplex, which will demonstrate that the ligand/receptor specificityexchanger will have an effect on the cell.

The next section describes characterization assays that are performed inanimals.

In Vivo Characterization Assays

Characterization assays also include experiments that evaluateligand/receptor specificity exchangers in vivo. There are many animalmodels that are suitable for evaluating the ability of a ligand/receptorspecificity exchanger to inhibit pathogenic infection. Mice arepreferred because they are easy to maintain and are susceptible tobacterial infection, viral infection, and cancer. Chimpanzees are alsopreferred because of their close genetic relationship to humans.

An approach to evaluate the efficacy of a ligand/receptor specificityexchanger in mice is provided in the next example.

EXAMPLE 3

To test the ability of a ligand/receptor specificity exchanger to treata bacterial infection the following characterization assay can beperformed. Several female CF-1 outbred mice (Charles RiversLaboratories) of approximately 8 weeks of age and 25 gram body mass arevaccinated with the antigenic domains of the ligand/receptor specificityexchangers to be tested. Preferably, the antigenic domains are coupledto a carrier and are administered with an adjuvant. For example, theantigenic domains can be fused to keyhole limpet hemocyanin or bovineserum albumin, which act as both a carrier and adjuvant or an adjuvantsuch as Freund's adjuvant, aluminum hydroxide, or lysolecithin can beused. Once a high titer of antibody to the antigenic domains can beverified by, for example, immunodiffusion or EIA, the immunized mice areinoculated intraperitoneally with overnight cultures of Staphylococcusaureus NTCC 10649. The inoculums are adjusted to yield approximately100×LD₅₀ or log 6.6 for S. aureus.

Serial dilutions of ligand/receptor specificity exchangers (e.g., theligand/receptor specificity exchangers provide in TABLE III) areformulated in sterile water for injection and are administered by thesubcutaneous (SC) or oral (PO) route at one and five hours postinfection. Concurrently with each trial, the challenge LD₅₀ is validatedby inoculation of untreated mice with log dilutions of the bacterialinoculum. Preferably, a five log dilution range of the bacterialchallenges is inoculated into five groups of ten mice each (ten mice perlog dilution). A mortality rate of 100% will be produced in all groupsof untreated mice at the 100×LD₅₀ challenge inoculum. Mice are monitoreddaily for mortality for seven days. The mean effective dose to protect50% of the mice (ED₅₀) can be calculated from cumulative mortality bylogarithmic-probit analysis of a plotted curve of survival versus dosageas described in Antimicrob. Agents Chemother. 31: 1768-1774 and Proc.Soc. Exp. Biol. Med. 1994, 57, 261-264, each of which are herebyexpressly incorporated by reference in their entireties. As one of skillin the art will appreciate, similar approaches can be used to test theability of ligand/receptor specificity exchangers to inhibit viralinfection and cancer.

The ligand/receptor specificity exchangers described herein can beformulated in pharmaceuticals and administered to subjects in need of anagent that inhibits the proliferation of a pathogen. The section belowdescribes several pharmaceuticals comprising ligand/receptor specificityexchangers that interact with a receptor on a pathogen.

Pharmaceuticals Comprising a Ligand/Receptor Specificity Exchanger thatInteracts with a Receptor on a Pathogen

The ligand/receptor specificity exchangers described herein are suitablefor incorporation into pharmaceuticals for administration to subjects inneed of a compound that treats or prevents infection by a pathogen.These pharmacologically active compounds can be processed in accordancewith conventional methods of galenic pharmacy to produce medicinalagents for administration to mammals including humans. The activeingredients can be incorporated into a pharmaceutical product with andwithout modification. Further, the manufacture of pharmaceuticals ortherapeutic agents that deliver the pharmacologically active compoundsof this invention by several routes are aspects of the presentinvention. For example, and not by way of limitation, DNA, RNA, andviral vectors having sequences encoding a ligand/receptor specificityexchanger that interacts with a receptor on a pathogen are used withembodiments of the invention. Nucleic acids encoding a ligand/receptorspecificity exchanger can be administered alone or in combination withother active ingredients.

The compounds can be employed in admixture with conventional excipients,i.e., pharmaceutically acceptable organic or inorganic carriersubstances suitable for parenteral, enteral (e.g., oral) or topicalapplication that do not deleteriously react with the pharmacologicallyactive ingredients described herein. Suitable pharmaceuticallyacceptable carriers include, but are not limited to, water, saltsolutions, alcohols, gum arabic, vegetable oils, benzyl alcohols,polyetylene glycols, gelatine, carbohydrates such as lactose, amylose orstarch, magnesium stearate, talc, silicic acid, viscous paraffin,perfume oil, fatty acid monoglycerides and diglycerides, pentaerythritolfatty acid esters, hydroxy methylcellulose, polyvinyl pyrrolidone, etc.Many more vehicles that can be used are described in Remmington'sPharmaceutical Sciences, 15th Edition, Easton:Mack Publishing Company,pages 1405-1412 and 1461-1487(1975) and The National Formulary XWV, 14thEdition, Washington, American Pharmaceutical Association (1975), hereinincorporated by reference. The pharmaceutical preparations can besterilized and if desired mixed with auxiliary agents, e.g., lubricants,preservatives, stabilizers, wetting agents, emulsifiers, salts forinfluencing osmotic pressure, buffers, coloring, flavoring and/oraromatic substances and the like so long as the auxiliary agents doesnot deleteriously react with the ligand/receptor specificity exchangers.

The effective dose and method of administration of a particularpharmaceutical having a ligand/receptor specificity exchanger can varybased on the individual needs of the patient and the treatment orpreventative measure sought. Therapeutic efficacy and toxicity of suchcompounds can be determined by standard pharmaceutical procedures incell cultures or experimental animals, e.g., ED50 (the dosetherapeutically effective in 50% of the population). For example, theeffective dose of a ligand/receptor specificity exchanger can beevaluated using the characterization assays described above. The dataobtained from these assays is then used in formulating a range of dosagefor use with other organisms, including humans. The dosage of suchcompounds lies preferably within a range of circulating concentrationsthat include the ED50 with no toxicity. The dosage varies within thisrange depending upon type of ligand/receptor specificity exchanger, thedosage form employed, sensitivity of the organism, and the route ofadministration.

Normal dosage amounts of a ligand/receptor specificity exchanger canvary from approximately 1 to 100,000 micrograms, up to a total dose ofabout 10 grams, depending upon the route of administration. Desirabledosages include about 250 μg-1 mg, about 50 mg-200 mg, and about 250mg-500 mg.

In some embodiments, the dose of a ligand/receptor specificity exchangerpreferably produces a tissue or blood concentration or both fromapproximately 0.1 μM to 500 mM. Desirable doses produce a tissue orblood concentration or both of about 1 to 800 μM. Preferable dosesproduce a tissue or blood concentration of greater than about 10 μM toabout 500 μM. Although doses that produce a tissue concentration ofgreater than 800μM are not preferred, they can be used. A constantinfusion of a ligand/receptor specificity exchanger can also be providedso as to maintain a stable concentration in the tissues as measured byblood levels.

The exact dosage is chosen by the individual physician in view of thepatient to be treated. Dosage and administration are adjusted to providesufficient levels of the active moiety or to maintain the desiredeffect. Additional factors that can be taken into account include theseverity of the disease, age of the organism being treated, and weightor size of the organism; diet, time and frequency of administration,drug combination(s), reaction sensitivities, and tolerance/response totherapy. Short acting pharmaceutical compositions are administered dailyor more frequently whereas long acting pharmaceutical compositions areadministered every 2 or more days, once a week, or once every two weeksor even less frequently.

Routes of administration of the pharmaceuticals include, but are notlimited to, topical, transdermal, parenteral, gastrointestinal,transbronchial, and transalveolar. Transdermal administration isaccomplished by application of a cream, rinse, gel, etc. capable ofallowing the ligand/receptor specificity exchangers to penetrate theskin. Parenteral routes of administration include, but are not limitedto, electrical or direct injection such as direct injection into acentral venous line, intravenous, intramuscular, intraperitoneal,intradermal, or subcutaneous injection. Gastrointestinal routes ofadministration include, but are not limited to, ingestion and rectal.Transbronchial and transalveolar routes of administration include, butare not limited to, inhalation, either via the mouth or intranasally.

Compositions having the ligand/receptor specificity exchangers describedherein that are suitable for transdermal or topical administrationinclude, but are not limited to, pharmaceutically acceptablesuspensions, oils, creams, and ointments applied directly to the skin orincorporated into a protective carrier such as a transdermal device(“transdermal patch”). Examples of suitable creams, ointments, etc. canbe found, for instance, in the Physician's Desk Reference. Examples ofsuitable transdermal devices are described, for instance, in U.S. Pat.No. 4,818,540 issued Apr. 4, 1989 to Chinen, et al., herein expresslyincorporated by reference in its entirety.

Compositions having pharmacologically active compounds that are suitablefor parenteral administration include, but are not limited to,pharmaceutically acceptable sterile isotonic solutions. Such solutionsinclude, but are not limited to, saline and phosphate buffered salinefor injection into a central venous line, intravenous, intramuscular,intraperitoneal, intradermal, or subcutaneous injection.

Compositions having pharmacologically active compounds that are suitablefor transbronchial and transalveolar administration include, but are notlimited to, various types of aerosols for inhalation. Devices suitablefor transbronchial and transalveolar administration of these are alsoembodiments. Such devices include, but are not limited to, atomizers andvaporizers. Many forms of currently available atomizers and vaporizerscan be readily adapted to deliver compositions having theligand/receptor specificity exchangers described herein.

Compositions having pharmacologically active compounds that are suitablefor gastrointestinal administration include, but not limited to,pharmaceutically acceptable powders, pills or liquids for ingestion andsuppositories for rectal administration. Due to the ease of use,gastrointestinal administration, particularly oral, is a preferredembodiment. Once the pharmaceutical comprising the ligand/receptorspecificity exchanger has been obtained, it can be administered to anorganism in need to treat or prevent pathogenic infection.

Aspects of the invention also include a coating for medical equipmentsuch as prosthetics, implants, and instruments. Coatings suitable foruse on medical devices can be provided by a gel or powder containing theligand/receptor specificity exchanger or by a polymeric coating intowhich a ligand/receptor specificity exchanger is suspended. Suitablepolymeric materials for coatings of devices are those that arephysiologically acceptable and through which a therapeutically effectiveamount of the ligand/receptor specificity exchanger can diffuse.Suitable polymers include, but are not limited to, polyurethane,polymethacrylate, polyamide, polyester, polyethylene, polypropylene,polystyrene, polytetrafluoroethylene, polyvinyl-chloride, celluloseacetate, silicone elastomers, collagen, silk, etc. Such coatings aredescribed, for instance, in U.S. Pat. No. 4,612,337, herein expresslyincorporated by reference in its entirety.

The section below describes methods of treating and preventing diseaseusing the ligand/receptor specificity exchangers described herein.

Treatment and Prevention of Disease Using a Ligand/receptor SpecificityExchanger

Pharmaceuticals comprising a ligand/receptor specificity exchanger canbe administered to a subject in need to treat and/or prevent infectionby a pathogen that has a receptor. Such subjects in need can includeindividuals at risk of contacting a pathogen or individuals who arealready infected by a pathogen. These individuals can be identified bystandard clinical or diagnostic techniques.

By one approach, for example, a subject suffering from a bacterialinfection is identified as a subject in need of an agent that inhibitsproliferation of a pathogen. This subject is then provided atherapeutically effective amount of ligand/receptor specificityexchanger. The ligand/receptor specificity exchanger used in this methodcomprises a specificity domain that interacts with a receptor present onthe bacteria (e.g., extracellular fibrinogen binding protein (Efb),collagen binding protein, vitronectin binding protein, laminin bindingprotein, plasminogen binding protein, thrombospondin binding protein,clumping factor A (ClfA), clumping factor B (ClfB), fibronectin bindingprotein, coagulase, and extracellular adherence protein). Theligand/receptor specificity exchanger also comprises an antigenic domainthat has an epitope of a pathogen or toxin, preferably, an epitoperecognized by high titer antibodies present in the subject in need. Itmay also be desired to screen the subject in need for the presence ofhigh titer antibodies that recognize the antigenic domain prior toproviding the subject the ligand/receptor specificity exchanger. Thisscreening can be accomplished by EIA or ELISA using immobilizedantigenic domain or ligand/receptor specificity exchanger, as describedabove.

Similarly a subject in need of an agent that inhibits viral infectioncan be administered a ligand/receptor specificity exchanger thatrecognizes a receptor present on the particular etiologic agent.Accordingly, a subject in need of an agent that inhibits viral infectionis identified by standard clinical or diagnostic procedures. Next, thesubject in need is provided a therapeutically effective amount of aligand/receptor specificity exchanger that interacts with a receptorpresent on the type of virus infecting the individual. As above, it maybe desired to determine whether the subject has a sufficient titer ofantibody to interact with the antigenic domain of the ligand/receptorspecificity exchanger prior to administering the ligand/receptorspecificity exchanger.

In the same vein, a subject in need of an agent that inhibits theproliferation of cancer can be administered a ligand/receptorspecificity exchanger that interacts with a receptor present on thecancer cell. For example, a subject in need of an agent that inhibitsproliferation of cancer is identified by standard clinical or diagnosticprocedures; then the subject in need is provided a therapeuticallyeffective amount of a ligandireceptor specificity exchanger thatinteracts with a receptor present on the cancer cells infecting thesubject. As noted above, it may be desired to determine whether thesubject has a sufficient titer of antibody to interact with theantigenic domain of the ligand/receptor specificity exchanger prior toadministering the ligand/receptor specificity exchanger.

Ligand/receptor specificity exchangers described herein can also beadministered to subjects as a prophylactic to prevent the onset ofdisease. Virtually anyone can be administered a ligand/receptorspecificity exchanger described herein for prophylactic purposes, (e.g.,to prevent a bacterial infection, viral infection, or cancer). It isdesired, however, that subjects at a high risk of contracting aparticular disease are identified and provided a ligand/receptorspecificity exchanger. Subjects at high risk of contracting a diseaseinclude individuals with a family history of disease , the elderly orthe young, or individuals that come in frequent contact with a pathogen(e.g., health care practitioners). Accordingly, subjects at risk ofbecoming infected by a pathogen that has a receptor are identified andthen are provided a prophylactically effective amount of ligand/receptorspecificity exchanger.

One prophylactic application for the a ligand/receptor specificityexchangers described herein concerns coating or cross-linking theligand/receptor specificity exchanger to a medical device or implant.Implantable medical devices tend to serve as foci for infection by anumber of bacterial species. Such device-associated infections arepromoted by the tendency of these organisms to adhere to and colonizethe surface of the device. Consequently, there is a considerable need todevelop surfaces that are less prone to promote the adverse biologicalreactions that typically accompany the implantation of a medical device.

By one approach, the medical device is coated in a solution ofcontaining a ligand/receptor specificity exchanger. Prior toimplantation, medical devices (e.g., a prosthetic valve) can be storedin a solution of ligand/receptor specificity exchangers, for example.Medical devices can also be coated in a powder or gel having aligand/receptor specificity exchanger. For example, gloves, condoms, andintrauterine devices can be coated in a powder or gel that contains aspecificity exchanger that interacts with a bacterial or viral receptor.Once implanted in the body, these ligand/receptor specificity exchangersprovide a prophylactic barrier to infection by a pathogen.

In some embodiments, the ligand/receptor specificity exchanger isimmobilized to the medical device. As described above, the medicaldevice is a support to which a ligand/receptor specificity exchanger canbe attached. Immobilization may occur by hydrophobic interaction betweenthe ligand/receptor specificity exchanger and the medical device but apreferable way to immobilize a ligand/receptor specificity exchanger toa medical device involves covalent attachment. For example, medicaldevices can be manufactured with a reactive group that interacts with areactive group present on the specificity exchanger.

By one approach, a periodate is combined with a ligand/receptorspecificity exchanger comprising a 2-aminoalcohol moiety to form analdehyde-functional exchanger in an aqueous solution having a pH betweenabout 4 and about 9 and a temperature between about 0 and about 50degrees Celsius. Next, the aldehyde-functional exchanger is combinedwith the biomaterial surface of a medical device that comprises aprimary amine moiety to immobilize the ligand/receptor specificityexchanger on the support surface through an imine moiety. Then, theimine moiety is reacted with a reducing agent to form an immobilizedligand/receptor specificity exchanger on the biomaterial surface througha secondary amine linkage. Other approaches for cross-linking moleculesto medical devices, (such as described in U.S. Pat. No. 6,017,741,herein expressly incorporated by reference in its entirety); can bemodified to immobilize the ligand/receptor specificity exchangerdescribed herein.

Although the invention has been described with reference to embodimentsand examples, it should be understood that various modifications can bemade without departing from the spirit of the invention. Accordingly,the invention is limited only by the following claims. All referencescited herein are hereby expressly incorporated by reference.

105 1 18 PRT Artificial Sequence Specificity domain peptide 1 Tyr GlyGlu Gly Gln Gln His His Leu Gly Gly Ala Lys Gln Ala Gly 1 5 10 15 AspVal 2 20 PRT Artificial Sequence Specificity domain peptide 2 Met SerTrp Ser Leu His Pro Arg Asn Leu Ile Leu Tyr Phe Tyr Ala 1 5 10 15 LeuLeu Phe Leu 20 3 19 PRT Artificial Sequence Specificity domain peptide 3Ile Leu Tyr Phe Tyr Ala Leu Leu Phe Leu Ser Thr Cys Val Ala Tyr 1 5 1015 Val Ala Thr 4 20 PRT Artificial Sequence Specificity domain peptide 4Ser Ser Thr Cys Val Ala Tyr Val Ala Thr Arg Asp Asn Cys Cys Ile 1 5 1015 Leu Asp Glu Arg 20 5 20 PRT Artificial Sequence Specificity domainpeptide 5 Arg Asp Asn Cys Cys Ile Leu Asp Glu Arg Phe Gly Ser Tyr CysPro 1 5 10 15 Thr Thr Cys Gly 20 6 20 PRT Artificial SequenceSpecificity domain peptide 6 Phe Gly Ser Tyr Cys Pro Thr Thr Cys Gly IleAla Asp Phe Leu Ser 1 5 10 15 Thr Tyr Gln Thr 20 7 20 PRT ArtificialSequence Specificity domain peptide 7 Ile Ala Asp Phe Leu Ser Thr TyrGln Thr Lys Val Asp Lys Asp Leu 1 5 10 15 Gln Ser Leu Glu 20 8 20 PRTArtificial Sequence Specificity domain peptide 8 Lys Val Asp Lys Asp LeuGln Ser Leu Glu Asp Ile Leu His Gln Val 1 5 10 15 Glu Asn Lys Thr 20 920 PRT Artificial Sequence Specificity domain peptide 9 Asp Ile Leu HisGln Val Glu Asn Lys Thr Ser Glu Val Lys Gln Leu 1 5 10 15 Ile Lys AlaIle 20 10 20 PRT Artificial Sequence Specificity domain peptide 10 SerGlu Val Lys Gln Leu Ile Lys Ala Ile Gln Leu Thr Tyr Asn Pro 1 5 10 15Asp Glu Ser Ser 20 11 20 PRT Artificial Sequence Specificity domainpeptide 11 Gln Leu Thr Tyr Asn Pro Asp Glu Ser Ser Lys Pro Asn Met IleAsp 1 5 10 15 Ala Ala Thr Leu 20 12 20 PRT Artificial SequenceSpecificity domain peptide 12 Lys Pro Asn Met Ile Asp Ala Ala Thr LeuLys Ser Arg Ile Met Leu 1 5 10 15 Glu Glu Ile Met 20 13 20 PRTArtificial Sequence Specificity domain peptide 13 Lys Ser Arg Ile MetLeu Glu Glu Ile Met Lys Tyr Glu Ala Ser Ile 1 5 10 15 Leu Thr His Asp 2014 20 PRT Artificial Sequence Specificity domain peptide 14 Lys Tyr GluAla Ser Ile Leu Thr His Asp Ser Ser Ile Arg Tyr Leu 1 5 10 15 Gln GluIle Tyr 20 15 20 PRT Artificial Sequence Specificity domain peptide 15Ser Ser Ile Arg Tyr Leu Gln Glu Ile Tyr Asn Ser Asn Asn Gln Lys 1 5 1015 Ile Val Asn Leu 20 16 20 PRT Artificial Sequence Specificity domainpeptide 16 Asn Ser Asn Asn Gln Lys Ile Val Asn Leu Lys Glu Lys Val AlaGln 1 5 10 15 Leu Glu Ala Gln 20 17 20 PRT Artificial SequenceSpecificity domain peptide 17 Cys Gln Glu Pro Cys Lys Asp Thr Val GlnIle His Asp Ile Thr Gly 1 5 10 15 Lys Asp Cys Gln 20 18 20 PRTArtificial Sequence Specificity domain peptide 18 Ile His Asp Ile ThrGly Lys Asp Cys Gln Asp Ile Ala Asn Lys Gly 1 5 10 15 Ala Lys Gln Ser 2019 20 PRT Artificial Sequence Specificity domain peptide 19 Asp Ile AlaAsn Lys Gly Ala Lys Gln Ser Gly Leu Tyr Phe Ile Lys 1 5 10 15 Pro LeuLys Ala 20 20 20 PRT Artificial Sequence Specificity domain peptide 20Gly Leu Tyr Phe Ile Lys Pro Leu Lys Ala Asn Gln Gln Phe Leu Val 1 5 1015 Tyr Cys Glu Ile 20 21 20 PRT Artificial Sequence Specificity domainpeptide 21 Asn Gln Gln Phe Leu Val Tyr Cys Glu Ile Asp Gly Ser Gly AsnGly 1 5 10 15 Trp Thr Val Phe 20 22 20 PRT Artificial SequenceSpecificity domain peptide 22 Asp Gly Ser Gly Asn Gly Trp Thr Val PheGln Lys Arg Leu Asp Gly 1 5 10 15 Ser Val Asp Phe 20 23 20 PRTArtificial Sequence Specificity domain peptide 23 Gln Lys Arg Leu AspGly Ser Val Asp Phe Lys Lys Asn Trp Ile Gln 1 5 10 15 Tyr Lys Glu Gly 2024 20 PRT Artificial Sequence Specificity domain peptide 24 Lys Lys AsnTrp Ile Gln Tyr Lys Glu Gly Phe Gly His Leu Ser Pro 1 5 10 15 Thr GlyThr Thr 20 25 20 PRT Artificial Sequence Specificity domain peptide 25Phe Gly His Leu Ser Pro Thr Gly Thr Thr Glu Phe Trp Leu Gly Asn 1 5 1015 Glu Lys Ile His 20 26 20 PRT Artificial Sequence Specificity domainpeptide 26 Glu Phe Trp Leu Gly Asn Glu Lys Ile His Leu Ile Ser Thr GlnSer 1 5 10 15 Ala Ile Pro Tyr 20 27 20 PRT Artificial SequenceSpecificity domain peptide 27 Leu Ile Ser Thr Gln Ser Ala Ile Pro TyrAla Leu Arg Val Glu Leu 1 5 10 15 Glu Asp Trp Asn 20 28 20 PRTArtificial Sequence Specificity domain peptide 28 Ala Leu Arg Val GluLeu Glu Asp Trp Asn Gly Arg Thr Ser Thr Ala 1 5 10 15 Asp Tyr Ala Met 2029 20 PRT Artificial Sequence Specificity domain peptide 29 Gly Arg ThrSer Thr Ala Asp Tyr Ala Met Phe Lys Val Gly Pro Glu 1 5 10 15 Ala AspLys Tyr 20 30 20 PRT Artificial Sequence Specificity domain peptide 30Phe Lys Val Gly Pro Glu Ala Asp Lys Tyr Arg Leu Thr Tyr Ala Tyr 1 5 1015 Phe Ala Gly Gly 20 31 20 PRT Artificial Sequence Specificity domainpeptide 31 Arg Leu Thr Tyr Ala Tyr Phe Ala Gly Gly Asp Ala Gly Asp AlaPhe 1 5 10 15 Asp Gly Phe Asp 20 32 20 PRT Artificial SequenceSpecificity domain peptide 32 Asp Ala Gly Asp Ala Phe Asp Gly Phe AspPhe Gly Asp Asp Pro Ser 1 5 10 15 Asp Lys Phe Phe 20 33 20 PRTArtificial Sequence Specificity domain peptide 33 Phe Gly Asp Asp ProSer Asp Lys Phe Phe Thr Ser His Asn Gly Met 1 5 10 15 Gln Phe Ser Thr 2034 20 PRT Artificial Sequence Specificity domain peptide 34 Thr Ser HisAsn Gly Met Gln Phe Ser Thr Trp Asp Asn Asp Asn Asp 1 5 10 15 Lys PheGlu Gly 20 35 20 PRT Artificial Sequence Specificity domain peptide 35Trp Asp Asn Asp Asn Asp Lys Phe Glu Gly Asn Cys Ala Glu Gln Asp 1 5 1015 Gly Ser Gly Trp 20 36 20 PRT Artificial Sequence Specificity domainpeptide 36 Asn Cys Ala Glu Gln Asp Gly Ser Gly Trp Trp Met Asn Lys CysHis 1 5 10 15 Ala Gly His Leu 20 37 20 PRT Artificial SequenceSpecificity domain peptide 37 Trp Met Asn Lys Cys His Ala Gly His LeuAsn Gly Val Tyr Tyr Gln 1 5 10 15 Gly Gly Thr Tyr 20 38 20 PRTArtificial Sequence Specificity domain peptide 38 Asn Gly Val Tyr TyrGln Gly Gly Thr Tyr Ser Lys Ala Ser Thr Pro 1 5 10 15 Asn Gly Tyr Asp 2039 20 PRT Artificial Sequence Specificity domain peptide 39 Ser Lys AlaSer Thr Pro Asn Gly Tyr Asp Asn Gly Ile Ile Trp Ala 1 5 10 15 Thr TrpLys Thr 20 40 20 PRT Artificial Sequence Specificity domain peptide 40Asn Gly Ile Ile Trp Ala Thr Trp Lys Thr Arg Trp Tyr Ser Met Lys 1 5 1015 Lys Thr Thr Met 20 41 20 PRT Artificial Sequence Specificity domainpeptide 41 Arg Trp Tyr Ser Met Lys Lys Thr Thr Met Lys Ile Ile Pro PheAsn 1 5 10 15 Arg Leu Thr Ile 20 42 27 PRT Artificial SequenceSpecificity domain peptide 42 Lys Ile Ile Pro Phe Asn Arg Leu Thr IleGly Glu Gly Gln Gln His 1 5 10 15 His Leu Gly Gly Ala Lys Gln Ala GlyAsp Val 20 25 43 17 PRT Artificial Sequence Antigenic domain peptide 43Gly Leu Tyr Ser Ser Ile Trp Leu Ser Pro Gly Arg Ser Tyr Phe Glu 1 5 1015 Thr 44 17 PRT Artificial Sequence Antigenic domain peptide 44 Tyr ThrAsp Ile Lys Tyr Asn Pro Phe Thr Asp Arg Gly Glu Gly Asn 1 5 10 15 Met 4517 PRT Artificial Sequence Antigenic domain peptide 45 Asp Gln Asn IleHis Met Asn Ala Arg Leu Leu Ile Arg Ser Pro Phe 1 5 10 15 Thr 46 17 PRTArtificial Sequence Antigenic domain peptide 46 Leu Ile Arg Ser Pro PheThr Asp Pro Gln Leu Leu Val His Thr Asp 1 5 10 15 Pro 47 17 PRTArtificial Sequence Antigenic domain peptide 47 Gln Lys Glu Ser Leu LeuPhe Pro Pro Val Lys Leu Leu Arg Arg Val 1 5 10 15 Pro 48 11 PRTArtificial Sequence Antigenic domain peptide 48 Pro Ala Leu Thr Ala ValGlu Thr Gly Ala Thr 1 5 10 49 8 PRT Artificial Sequence Antigenic domainpeptide 49 Ser Thr Leu Val Pro Glu Thr Thr 1 5 50 13 PRT ArtificialSequence Antigenic domain peptide 50 Thr Pro Pro Ala Tyr Arg Pro Pro AsnAla Pro Ile Leu 1 5 10 51 9 PRT Artificial Sequence Antigenic domainpeptide 51 Glu Ile Pro Ala Leu Thr Ala Val Glu 1 5 52 10 PRT ArtificialSequence Antigenic domain peptide 52 Leu Glu Asp Pro Ala Ser Arg Asp LeuVal 1 5 10 53 8 PRT Artificial Sequence Antigenic domain peptide 53 HisArg Gly Gly Pro Glu Glu Phe 1 5 54 7 PRT Artificial Sequence Antigenicdomain peptide 54 His Arg Gly Gly Pro Glu Glu 1 5 55 17 PRT ArtificialSequence Antigenic domain peptide 55 Val Leu Ile Cys Gly Glu Asn Thr ValSer Arg Asn Tyr Ala Thr His 1 5 10 15 Ser 56 17 PRT Artificial SequenceAntigenic domain peptide 56 Lys Ile Asn Thr Met Pro Pro Phe Leu Asp ThrGlu Leu Thr Ala Pro 1 5 10 15 Ser 57 17 PRT Artificial SequenceAntigenic domain peptide 57 Pro Asp Glu Lys Ser Gln Arg Glu Ile Leu LeuAsn Lys Ile Ala Ser 1 5 10 15 Tyr 58 17 PRT Artificial SequenceAntigenic domain peptide 58 Thr Ala Thr Thr Thr Thr Tyr Ala Tyr Pro GlyThr Asn Arg Pro Pro 1 5 10 15 Val 59 8 PRT Artificial Sequence Antigenicdomain peptide 59 Ser Thr Pro Leu Pro Glu Thr Thr 1 5 60 26 PRTArtificial Sequence Ligand/Receptor specificity exchanger peptide 60 TyrGly Glu Gly Gln Gln His His Leu Gly Gly Ala Lys Gln Ala Gly 1 5 10 15Asp Val His Arg Gly Gly Pro Glu Glu Phe 20 25 61 25 PRT ArtificialSequence Ligand/Receptor specificity exchanger peptide 61 Tyr Gly GluGly Gln Gln His His Leu Gly Gly Ala Lys Gln Ala Gly 1 5 10 15 Asp ValHis Arg Gly Gly Pro Glu Glu 20 25 62 26 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 62 Tyr Gly Glu Gly Gln GlnHis His Leu Gly Gly Ala Lys Gln Ala Gly 1 5 10 15 Asp Val Ser Thr ProLeu Pro Glu Thr Thr 20 25 63 27 PRT Artificial Sequence Ligand/Receptorspecificity exchanger peptide 63 Met Ser Trp Ser Leu His Pro Arg Asn LeuIle Leu Tyr Phe Tyr Ala 1 5 10 15 Leu Leu Phe Leu His Arg Gly Gly ProGlu Glu 20 25 64 26 PRT Artificial Sequence Ligand/Receptor specificityexchanger peptide 64 Ile Leu Tyr Phe Tyr Ala Leu Leu Phe Leu Ser Thr CysVal Ala Tyr 1 5 10 15 Val Ala Thr His Arg Gly Gly Pro Glu Glu 20 25 6527 PRT Artificial Sequence Ligand/Receptor specificity exchanger peptide65 Ser Ser Thr Cys Val Ala Tyr Val Ala Thr Arg Asp Asn Cys Cys Ile 1 510 15 Leu Asp Glu Arg His Arg Gly Gly Pro Glu Glu 20 25 66 27 PRTArtificial Sequence Ligand/Receptor specificity exchanger peptide 66 ArgAsp Asn Cys Cys Ile Leu Asp Glu Arg Phe Gly Ser Tyr Cys Pro 1 5 10 15Thr Thr Cys Gly His Arg Gly Gly Pro Glu Glu 20 25 67 27 PRT ArtificialSequence Ligand/Receptor specificity exchanger peptide 67 Phe Gly SerTyr Cys Pro Thr Thr Cys Gly Ile Ala Asp Phe Leu Ser 1 5 10 15 Thr TyrGln Thr His Arg Gly Gly Pro Glu Glu 20 25 68 27 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 68 Ile Ala Asp Phe Leu SerThr Tyr Gln Thr Lys Val Asp Lys Asp Leu 1 5 10 15 Gln Ser Leu Glu HisArg Gly Gly Pro Glu Glu 20 25 69 27 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 69 Lys Val Asp Lys Asp LeuGln Ser Leu Glu Asp Ile Leu His Gln Val 1 5 10 15 Glu Asn Lys Thr HisArg Gly Gly Pro Glu Glu 20 25 70 27 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 70 Asp Ile Leu His Gln ValGlu Asn Lys Thr Ser Glu Val Lys Gln Leu 1 5 10 15 Ile Lys Ala Ile HisArg Gly Gly Pro Glu Glu 20 25 71 27 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 71 Ser Glu Val Lys Gln LeuIle Lys Ala Ile Gln Leu Thr Tyr Asn Pro 1 5 10 15 Asp Glu Ser Ser HisArg Gly Gly Pro Glu Glu 20 25 72 27 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 72 Gln Leu Thr Tyr Asn ProAsp Glu Ser Ser Lys Pro Asn Met Ile Asp 1 5 10 15 Ala Ala Thr Leu HisArg Gly Gly Pro Glu Glu 20 25 73 27 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 73 Lys Pro Asn Met Ile AspAla Ala Thr Leu Lys Ser Arg Ile Met Leu 1 5 10 15 Glu Glu Ile Met HisArg Gly Gly Pro Glu Glu 20 25 74 27 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 74 Lys Ser Arg Ile Met LeuGlu Glu Ile Met Lys Tyr Glu Ala Ser Ile 1 5 10 15 Leu Thr His Asp HisArg Gly Gly Pro Glu Glu 20 25 75 27 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 75 Lys Tyr Glu Ala Ser IleLeu Thr His Asp Ser Ser Ile Arg Tyr Leu 1 5 10 15 Gln Glu Ile Tyr HisArg Gly Gly Pro Glu Glu 20 25 76 27 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 76 Ser Ser Ile Arg Tyr LeuGln Glu Ile Tyr Asn Ser Asn Asn Gln Lys 1 5 10 15 Ile Val Asn Leu HisArg Gly Gly Pro Glu Glu 20 25 77 27 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 77 Asn Ser Asn Asn Gln LysIle Val Asn Leu Lys Glu Lys Val Ala Gln 1 5 10 15 Leu Glu Ala Gln HisArg Gly Gly Pro Glu Glu 20 25 78 27 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 78 Cys Gln Glu Pro Cys LysAsp Thr Val Gln Ile His Asp Ile Thr Gly 1 5 10 15 Lys Asp Cys Gln HisArg Gly Gly Pro Glu Glu 20 25 79 27 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 79 Ile His Asp Ile Thr GlyLys Asp Cys Gln Asp Ile Ala Asn Lys Gly 1 5 10 15 Ala Lys Gln Ser HisArg Gly Gly Pro Glu Glu 20 25 80 27 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 80 Asp Ile Ala Asn Lys GlyAla Lys Gln Ser Gly Leu Tyr Phe Ile Lys 1 5 10 15 Pro Leu Lys Ala HisArg Gly Gly Pro Glu Glu 20 25 81 27 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 81 Gly Leu Tyr Phe Ile LysPro Leu Lys Ala Asn Gln Gln Phe Leu Val 1 5 10 15 Tyr Cys Glu Ile HisArg Gly Gly Pro Glu Glu 20 25 82 27 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 82 Asn Gln Gln Phe Leu ValTyr Cys Glu Ile Asp Gly Ser Gly Asn Gly 1 5 10 15 Trp Thr Val Phe HisArg Gly Gly Pro Glu Glu 20 25 83 27 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 83 Asp Gly Ser Gly Asn GlyTrp Thr Val Phe Gln Lys Arg Leu Asp Gly 1 5 10 15 Ser Val Asp Phe HisArg Gly Gly Pro Glu Glu 20 25 84 27 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 84 Gln Lys Arg Leu Asp GlySer Val Asp Phe Lys Lys Asn Trp Ile Gln 1 5 10 15 Tyr Lys Glu Gly HisArg Gly Gly Pro Glu Glu 20 25 85 27 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 85 Lys Lys Asn Trp Ile GlnTyr Lys Glu Gly Phe Gly His Leu Ser Pro 1 5 10 15 Thr Gly Thr Thr HisArg Gly Gly Pro Glu Glu 20 25 86 27 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 86 Phe Gly His Leu Ser ProThr Gly Thr Thr Glu Phe Trp Leu Gly Asn 1 5 10 15 Glu Lys Ile His HisArg Gly Gly Pro Glu Glu 20 25 87 27 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 87 Glu Phe Trp Leu Gly AsnGlu Lys Ile His Leu Ile Ser Thr Gln Ser 1 5 10 15 Ala Ile Pro Tyr HisArg Gly Gly Pro Glu Glu 20 25 88 27 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 88 Leu Ile Ser Thr Gln SerAla Ile Pro Tyr Ala Leu Arg Val Glu Leu 1 5 10 15 Glu Asp Trp Asn HisArg Gly Gly Pro Glu Glu 20 25 89 27 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 89 Ala Leu Arg Val Glu LeuGlu Asp Trp Asn Gly Arg Thr Ser Thr Ala 1 5 10 15 Asp Tyr Ala Met HisArg Gly Gly Pro Glu Glu 20 25 90 27 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 90 Gly Arg Thr Ser Thr AlaAsp Tyr Ala Met Phe Lys Val Gly Pro Glu 1 5 10 15 Ala Asp Lys Tyr HisArg Gly Gly Pro Glu Glu 20 25 91 27 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 91 Phe Lys Val Gly Pro GluAla Asp Lys Tyr Arg Leu Thr Tyr Ala Tyr 1 5 10 15 Phe Ala Gly Gly HisArg Gly Gly Pro Glu Glu 20 25 92 27 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 92 Arg Leu Thr Tyr Ala TyrPhe Ala Gly Gly Asp Ala Gly Asp Ala Phe 1 5 10 15 Asp Gly Phe Asp HisArg Gly Gly Pro Glu Glu 20 25 93 27 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 93 Asp Ala Gly Asp Ala PheAsp Gly Phe Asp Phe Gly Asp Asp Pro Ser 1 5 10 15 Asp Lys Phe Phe HisArg Gly Gly Pro Glu Glu 20 25 94 27 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 94 Phe Gly Asp Asp Pro SerAsp Lys Phe Phe Thr Ser His Asn Gly Met 1 5 10 15 Gln Phe Ser Thr HisArg Gly Gly Pro Glu Glu 20 25 95 27 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 95 Thr Ser His Asn Gly MetGln Phe Ser Thr Trp Asp Asn Asp Asn Asp 1 5 10 15 Lys Phe Glu Gly HisArg Gly Gly Pro Glu Glu 20 25 96 27 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 96 Trp Asp Asn Asp Asn AspLys Phe Glu Gly Asn Cys Ala Glu Gln Asp 1 5 10 15 Gly Ser Gly Trp HisArg Gly Gly Pro Glu Glu 20 25 97 27 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 97 Asn Cys Ala Glu Gln AspGly Ser Gly Trp Trp Met Asn Lys Cys His 1 5 10 15 Ala Gly His Leu HisArg Gly Gly Pro Glu Glu 20 25 98 27 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 98 Trp Met Asn Lys Cys HisAla Gly His Leu Asn Gly Val Tyr Tyr Gln 1 5 10 15 Gly Gly Thr Tyr HisArg Gly Gly Pro Glu Glu 20 25 99 27 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 99 Asn Gly Val Tyr Tyr GlnGly Gly Thr Tyr Ser Lys Ala Ser Thr Pro 1 5 10 15 Asn Gly Tyr Asp HisArg Gly Gly Pro Glu Glu 20 25 100 27 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 100 Ser Lys Ala Ser ThrPro Asn Gly Tyr Asp Asn Gly Ile Ile Trp Ala 1 5 10 15 Thr Trp Lys ThrHis Arg Gly Gly Pro Glu Glu 20 25 101 27 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 101 Asn Gly Ile Ile TrpAla Thr Trp Lys Thr Arg Trp Tyr Ser Met Lys 1 5 10 15 Lys Thr Thr MetHis Arg Gly Gly Pro Glu Glu 20 25 102 27 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 102 Arg Trp Tyr Ser MetLys Lys Thr Thr Met Lys Ile Ile Pro Phe Asn 1 5 10 15 Arg Leu Thr IleHis Arg Gly Gly Pro Glu Glu 20 25 103 34 PRT Artificial SequenceLigand/Receptor specificity exchanger peptide 103 Lys Ile Ile Pro PheAsn Arg Leu Thr Ile Gly Glu Gly Gln Gln His 1 5 10 15 His Leu Gly GlyAla Lys Gln Ala Gly Asp Val His Arg Gly Gly Pro 20 25 30 Glu Glu 104 13PRT IArtificial Sequence Integrin specific ligand/receptor specificityexchanger peptide 104 Gly Arg Gly Asp Ser Pro His Arg Gly Gly Pro GluGlu 1 5 10 105 13 PRT Artificial Sequence Integrin specificligand/receptor specificity exchanger peptide 105 Trp Ser Arg Gly AspTrp His Arg Gly Gly Pro Glu Glu 1 5 10

What is claimed is:
 1. A ligand/receptor specificity exchangercomprising: at least one specificity domain comprising a first peptide,which comprises a ligand for a receptor; and at least one antigenicdomain joined to said specificity domain, wherein said antigenic domaincomprises a second peptide, which comprises an epitope of a pathogen ortoxin and wherein said first and second peptides are from differentproteins.
 2. A ligand receptor specificity exchanger comprising: atleast one specificity domain comprising a ligand for a receptor; and atleast one antigenic domain joined to said specificity domain, whereinsaid antigenic domain comprises an epitope of a pathogen or toxin andwherein the sequence of said ligand/receptor specificity exchanger isselected from the group consisting of SEQ. ID. No. 60, SEQ. ID. No. 61,SEQ. ID. No. 62, SEQ. ID. No. 63, SEQ. ID. No. 64, SEQ. ID. No. 65, SEQ.ID. No. 66, SEQ. ID. No. 67, SEQ. ID. No. 68, SEQ. ID. No. 69, SEQ. ID.No. 70, SEQ. ID. No. 71, SEQ. ID. No. 72, SEQ. ID. No. 73, SEQ. ID. No.74, SEQ. ID. No. 75, SEQ. ID. No. 76, SEQ. ID. No. 77, SEQ. ID. No. 78,SEQ. ID. No. 79, SEQ. ID. No. 80, SEQ. ID. No. 81, SEQ. ID. No. 82, SEQ.ID. No. 83, SEQ. ID. No. 84, SEQ. ID. No. 85, SEQ. ID. No. 86, SEQ. ID.No. 87, SEQ. ID. No. 88, SEQ. ID. No. 89, SEQ. ID. No. 90, SEQ. ID. No.91, SEQ. ID. No. 92, SEQ. ID. No. 93, SEQ. ID. No. 94, SEQ. ID. No. 95,SEQ. ID. No. 96, SEQ. ID. No. 97, SEQ. ID. No. 98, SEQ. ID. No. 99, SEQ.ID. No. 100, SEQ. ID. No. 101, SEQ. ID. No. 102, SEQ. ID. No. 103, SEQ.ID. No. 104, and SEQ. ID. No.
 105. 3. The ligand/receptor specificityexchanger of claim 1, wherein said specificity domain is at least 3amino acids in length.
 4. The ligand/receptor specificity exchanger ofclaim 1, wherein said specificity domain is at least 8 amino acids inlength.
 5. The ligand/receptor specificity exchanger of claim 1, whereinsaid specificity domain is at least 20 amino acids in length.
 6. Theligand/receptor specificity exchanger of claim 1, wherein said antigenicdomain is at least 3 amino acids in length.
 7. The ligand/receptorspecificity exchanger of claim 1, wherein said antigenic domain is atleast 5 and less than 35 amino acids in length.
 8. The ligand/receptorspecificity exchanger of claim 1, wherein said first peptide comprises aligand for a bacterial adhesion receptor.
 9. The ligand/receptorspecificity exchanger of claim 4, wherein said first peptide is afragment of fibrinogen.
 10. The ligand/receptor specificity exchanger ofclaim 5, wherein said first peptide is a fragment of fibrinogen.
 11. Theligand/receptor specificity exchanger of claim 8, wherein said bacterialadhesion receptor is a Staphylococcal adhesion receptor.
 12. Theligand/receptor specificity exchanger of claim 1, wherein said epitopeof a pathogen or toxin is selected from the group consisting of a herpessimplex virus protein, a hepatitis B virus protein, a TT virus protein,and a poliovirus protein.
 13. The ligand/receptor specificity exchangerof claim 7, wherein said epitope of a pathogen or toxin is selected fromthe group consisting of a herpes simplex virus protein, a hepatitis Bvirus protein, a TT virus protein, and a poliovirus protein.
 14. Theligand/receptor specificity exchanger of claim 1, wherein saidspecificity domain comprises at least three consecutive amino acids of apeptide that is selected from the group consisting of an extracellularmatrix protein, a ligand for a receptor on a virus, and a ligand for areceptor on a cancer cell.
 15. The ligand/receptor specificity exchangerof claim 14, wherein said peptide is an extracellular matrix proteinselected from the group consisting of fibrinogen, collagen, vitronectin,laminin, plasminogen, thrombospondin, and fibronectin.
 16. Theligand/receptor specificity exchanger of claim 14, wherein said peptideis a ligand for a receptor on a virus selected from the group consistingof T4 glycoprotein and hepatitis B viral envelope protein.
 17. Theligand/receptor specificity exchanger of claim 14, wherein said peptideis a ligand for a receptor on a cancer cell selected from the groupconsisting of a ligand for HER-2/neu, and a ligand for an integrinreceptor.
 18. The ligand/receptor specificity exchanger of claim 1,wherein said specificity domain comprises at least one sequence that isa member selected from the group consisting of SEQ. ID. No. 1, SEQ. ID.No. 2, SEQ. ID. No. 3, SEQ. ID. No. 4, SEQ. ID. No. 5, SEQ. ID. No. 6,SEQ. ID. No. 7, SEQ. ID. No. 8, SEQ. ID. No. 9, SEQ. ID. No. 10, SEQ.ID. No. 11, SEQ. ID. No. 12, SEQ. ID. No. 13, SEQ. ID. No. 14, SEQ. ID.No. 15, SEQ. ID. No. 16, SEQ. ID. No. 17, SEQ. ID. No. 18, SEQ. ID. No.19, SEQ. ID. No. 20, SEQ. ID. No. 21, SEQ. ID. No. 22, SEQ. ID. No. 23,SEQ. ID. No. 24, SEQ. ID. No. 25, SEQ. ID. No. 26, SEQ. ID. No. 27, SEQ.ID. No. 28, SEQ. ID. No. 29, SEQ. ID. No. 30, SEQ. ID. No. 31, SEQ. ID.No. 32, SEQ. ID. No. 33, SEQ. ID. No. 34, SEQ. ID. No. 35, SEQ. ID. No.36, SEQ. ID. No. 37, SEQ. ID. No. 38, SEQ. ID. No. 39, SEQ. ID. No. 40,SEQ. ID. No. 41, and SEQ. ID. No.
 42. 19. The ligand/receptorspecificity exchanger of claim 15, wherein said extracellular matrixprotein comprises at least 3 amino acids of the alpha-chain offibrinogen.
 20. The ligand/receptor specificity exchanger of claim 1,wherein said ligand comprises the sequence Arginine-Glycine-Aspartate(RGD).
 21. The ligand/receptor specificity exchanger of claim 1, whereinsaid receptor is on a pathogen.
 22. The ligand/receptor specificityexchanger of claim 21, wherein said pathogen is a Staphylococcus. 23.The ligand/receptor specificity exchanger of claim 1, wherein saidreceptor is a bacterial adhesion receptor.
 24. The ligand/receptorspecificity exchanger of claim 23, wherein said bacterial adhesionreceptor is selected from the group consisting of vitronectin bindingprotein, laminin binding protein, plasminogen binding protein,thrombospondin binding protein, clumping factor A (ClfA), clumpingfactor B (ClfB), fibronectin binding protein, coagulase, andextracellular adherence protein.
 25. The ligand/receptor specificityexchanger of claim 1, wherein said antigenic domain comprises at leastthree amino acids of a peptide selected from the group consisting of aherpes simplex virus protein, a hepatitis B virus protein, a TT virusprotein, and a poliovirus protein.
 26. The ligand/receptor specificityexchanger of claim 1, wherein said antigenic domain is a herpes simplexvirus protein comprising at least one sequence selected from the groupconsisting of SEQ. ID. No. 53 and SEQ. ID. No.
 54. 27. Theligand/receptor specificity exchanger of claim 1, wherein said antigenicdomain is a hepatitis B virus protein comprising at least one sequenceselected from the group consisting of SEQ. ID. No. 49, SEQ. ID. No. 50,SEQ. ID. No. 52, and SEQ. ID. No.
 59. 28. The ligand/receptorspecificity exchanger of claim 1, wherein said antigenic domain is a TTvirus protein comprising at least one sequence selected from the groupconsisting of SEQ. ID. No. 43, SEQ. ID. No. 44, SEQ. ID. No. 45, SEQ.ID. No. 46, SEQ. ID. No. 47, SEQ. ID. No. 55, SEQ. ID. No. 56, SEQ. ID.No. 57, and SEQ. ID. No.
 58. 29. The ligand/receptor specificityexchanger of claim 1, wherein said antigenic domain is a polio virusprotein comprising at least one sequence selected from the groupconsisting of SEQ. ID. No. 48, and SEQ. ID. No.
 51. 30. Theligand/receptor specificity exchanger of claim 1, wherein said antigenicdomain interacts with a high-titer antibody.
 31. The ligand/receptorspecificity exchanger of claim 30, wherein said antigenic domainspecifically binds to an antibody present in animal serum that has beendiluted to between approximately 1:100 to 1:1000 or greater.
 32. Theligand/receptor specificity exchanger of claim 1, wherein said firstpeptide comprises at least 3 consecutive amino acids of fibrinogen. 33.The ligand/receptor specificity exchanger of claim 1, wherein saidspecificity domain is at least 5 and less than 35 amino acids in length.34. The ligand/receptor specificity exchanger of claim 1, wherein saidspecificity domain and said antigenic domain are at least 5 and lessthan 35 amino acids in length.